Novel esters and derivatives

ABSTRACT

Novel aliphatic hydrocarbon esters, acids and alcohols having a backbone of at least 12 carbon atoms, a lower alkyl group at C-3, C-7 and C-11 and unsaturation or saturation at C-2,3, C-6,7 and/or C-10,11 which are substituents with, for example, halo, hydroxy, methylene, oxido, dihalo-methylene, and the like, and the esters and ethers of said hydroxy substituent useful as arthropod maturation inhibitors.

United States Patent Siddall et al.

[ 51 June 20, 1972 [54] NOVEL ESTERS AND DERIVATIVES [72] Inventors:John B. Siddall, Palo Alto, Calif.; Jeans Pierre Calame, Locamo,Switzerland [73] Assignee: Zoecon Corporation, Palo Alto, Calif.

[22] Filed: July 22, 1969 [21] App1.N0.: 843,818

Related us. Application Data [52] US. Cl. ..260/410.9 R, 260/413,260/468 P, 260/514 P, 260/294.3, 260/340.9, 260/345.7,

R, 260/473 C, 260/476 R, 260/482 R, 260/484 R,

260/486 R, 260/487, 260/488 H, 260/488 R,

260/493 R, 260/611 R, 260/612 D, 260/614 R,

[51] Int. Cl. ..C07c 69/74, C07c 61/16, AOln 9/24 [58] Field ofSearch..260/410.9,4l3,408,405,468 P, 260/514 P [56] References Clted UNITEDSTATES PATENTS 3,413,351 11/1968 Eschenmoser et al ..260/586 PrimaryExaminer-Lewis Gotts Assistant ExaminerDiana G. Rivers AttorneyDonald W.Erickson [57] ABSTRACT Novel aliphatic hydrocarbon esters, acids andalcohols having a backbone of at least 12 carbon atoms, a lower alkylgroup at C-3, C-7 and C-1 1 and unsaturation or saturation at C-2,3, C-6,7 and/or C-10,11 which are substituents with, for example, halo,hydroxy, methylene, oxido, dihalo-methylene, and the like, and theesters and ethers of said hydroxy substituent useful as arthropodmaturation inhibitors.

13 Claims, No Drawings NOVEL ESTERS AND DERIVATIVES This is acontinuation-in-part of U.S. application Ser. No. 800,266, filed Feb.18, 1969, which is a continuation-in-part of U.S. application Ser. No.618,351, filed Feb. 24, 1967, which, in turn, is a continuation-in-partof the following U.S. applications: Ser. No. 579,490, filed Sept. 15,1966; Ser. No. 590,195, filed Oct. 28, 1966; Ser. No. 592,324, filedNov. 7, 1966; Ser. No. 594,664, filed Nov. 16, 1966; Ser. No. 605,566,filed Dec. 29, 1966; and Ser. No. 605,578, filed Dec. 29, 1966, each nowabandoned.

This invention relates to novel aliphatic hydrocarbon ester derivativesand to processes for their preparation.

More particularly, the present invention relates to novel substitutedaliphatic hydrocarbon esters, substituted aliphatic hydrocarbon acidsand substituted aliphatic hydrocarbon alcohols (and the ethers andesters of said alcohols) having a backbone chain of 12 to 17 carbonatoms and a lower alkyl group at positions C-3, C-7 and C-1 1. Thesesubstituted aliphatic hydrocarbons can be prepared according to severalmethods described hereinafter. One method is to first prepare asubstituted aliphatic hydrocarbon ester and then convert the substitutedester into the acid or alcohol to obtain novel substituted aliphatichydrocarbon acids and alcohols (the alcohol, thereafter, can beconverted into the ether or ester). Altematively, an unsubstitutedaliphatic hydrocarbon ester is first converted into the correspondingacid or alcohol and thereafter the acid or alcohol is substitutedaccording to the procedures described hereinafter.

' The terms aliphatic hydrocarbon ester, aliphatic hydrocarbon acid, andaliphatic hydrocarbon alcohol," as used herein, refers to compoundscharacterized by the following fonnula:

wherein each of R, R, R and R is a lower alkyl group and R representsthe group -0R A a-on 1 wherein,

each of R- R R and R is lower alkyl; Z is hydrogen, hydroxy and ethersthereof, bromo, chloro or fluoro;

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro,fluoro, or, when taken together with Z, is a carbon-carbon double bondbetween C-2,3 or one of the groups in which X is chloro or fluoto;

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro orfluoro;

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro,fluoro, or, when taken together with Z, is a carbon-carbon double bondbetween C-6,7 or one of the groups 0, 0ir o012 or \()F1;

Z" is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro orfluoro;

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro,fluoro, or, when taken together with Z', is a in which X is chloro orfluoro; and p R is the group COOR' or CH OR" in which R is hydrogen orlower alkyl and R is hydrogen, lower alkyl or cabboxylic acyl group; andthe acid addition salts of the free acids, provided that when Z ishydrogen then Z is hydrogen.

Included within the present invention are the alkali metal and alkalineearth metal salts of the substituted aliphatic hydrocarbon acids. Thesalts of these acids include sodium, potassium, calcium, magnesium,barium, and the like.

As indicated above, the novel substituted aliphatic hydrocarbon esters,acids and alcohols (including the esters and ethers of said alcohols)can be derived from the compounds of formula XV. The compounds offormula XV can be prepared according to a process outlined as followswherein R, R, R and R are as defined above, Alk is a lower alkyl groupand D is phenyl.

In the practice of the above process (1- X), a dialkyl ketone (I) isreacted with an equal molar quantity, preferably an excess, of theWittig reagent of Formula II in an organic solvent, e.g., dimethylsulfoxide, at reflux temperatures to furnish the correspondingsubstituted Wittig reaction adduct of Formula Ill.

The Wittig reagent of Formula II can be prepared by conventionalprocedures, such as is described by Tripett, Advances in OrganicChemistry, Vol. 1, pp. 83-102, Trippett, Quarterly Review, Vol. 16-17,pp. 406-410; and Greenwald et al., Journal ofOrganic Chemistry 28, 1128(1963) from the 4-ethylene ketal of a 1-halo-4-alkanone .by treatmentwith triphenylphosphinc followed by treatment with butyl or phenyllithium.

The 4-ethylene ketal of the 1-halo-4-alkanone is obtained by subjectingthe 4-keto compound to conventional ketalysis with ethylene glycol inbenzene in the presence of an aryl sulfonic acid. The 1-halo-4-a1kanone,particularly the l-bromo derivative, can be prepared by known proceduressuch as that described in German Pat. No. 801,276 (Dec. 28, 1950), videChemical Abstracts 45, 2972h and by Jager et al., Arch. Pharm. 293, 896(1960), vide Chemical Abstracts 55, 3470g. Briefly, these proceduresinvolve treating butyrolactone with the desired alkyl alkanoate toprovide the corresponding aacylbutyrolactone adduct. Treatment of thelatter adduct with alkali metal halide, particularly sodium bromide, inaqueous sulfuric acid then provides the correspondingl-bromo-4-alkanone. Thus butyrolactone when treated with ethyl acetategives a-acetylbutyrolactone which is, in turn, converted tolbromo-4-pentanone.

Hydrolysis of the Wittig reaction adduct (III) with aqueous acid affordsthe free ketone (IV).

By repeating the Wittig reaction just described on the thus formedketone (IV) with the Wittig reagent (V) (prepared as described above),the corresponding diene adduct (V1) is obtained which is then hydrolyzedwith aqueous acid to the dienone (VII).

The dienone of Formula Vll is then converted into the trienoate ofFormula Vlll by treatment with a diethyl carboalkoxymethylphosphonate,such as diethyl carbomethoxymethylphosphonate '(VlII; Alk is methyl), inthe presence of an alkali metal hydride, e.g., sodium hydride.

The aliphatic hydrocarbon ester (trienoate) of Formula VlIl can then beconverted into the corresponding aliphatic hydrocarbon acid of FormulaXX by treatment with an alkali metal salt, e,g., sodium carbonate, inaqueous alcohol, e.g., aqueous methanol or into the correspondingaliphatic hydrocarbon alcohol of Formula X by trgatment with, forexample, lithium aluminum hydride.

Typical of the substituted aliphatic hydrocarbon esters, acids andalcohols which can be obtained from the above prepared startingmaterials are those of the following formulas:

(XVI) wherein R is hydrogen or lower alkyl; each of R, R, R and R islower alkyl;

Z is hydrogen, hydroxy, chloro, fluoro or bromo;

Z is hydrogen, hydroxy, lower alkoxy, chloro, fluoro, or bromo, or whentaken together with Z, a carbon-carbon double bond or one of the groupsO, \CH2, \COIQ or CF 7' provided that when Z is hydroxy, chloro, fluoroor bromo, Z is other than hydrogen and when Z is hydrogen, Z ishydrogen;

Z is defined the same as Z; and Z is defined the same as Z and Ztogether with Z is defined the same as Z together with Z.

wherein, R, R, R and R are defined the same as above;

2" is hydrogen, hydroxy, chloro, fluoro or bromo; Z" is hydrogen,hydroxy, lower alkoxy, chloro, fluoro, or bromo, or when taken togetherwith 2 a group, provided that when Z is hydroxy, chloro, fluoro orbromo, Z" is other than hydrogen and when Z" is hydrogen, 2 is hydrogen;

Z is defined the same as Z Z' is defined the same as Z" together with Z"is defined the same as Z" together with Z'; and R is the group COOR' or-CH,OR", wherein R is hydrogen or lower alkyl and R" is hydrogen loweralkyl or a carboxylic acyl group. I

wherein R, R R, R, Z, Z, Z and Z are as defined above in connection withFormula XVI; R" is hydrogen, lower alkyl,

or a carboxylic acyl group; and A is methylene, difluoromethylene, ordichloromethylene.

wherein, in the above formulas XlX through XXVlII,

each of R, R, R", R, R R and R is as defined above; R is hydrogen, loweralkyl or a carboxylic acyl group;

R is oxa, methylene, difluoromethylene, or dichloromethylene;

each of R and R is a lower alkyl of two to six carbon atoms;

and X is chloro, fluoro or bromo.

The term lower alkyl, as used herein, refers to straight or branchedchain saturated aliphatic hydrocarbons having a chain length of one tosix carbon atoms, e.g., methyl, ethyl, propyl, i-propyl, s-butyl,i-butyl, and the like. The term lower alkoxy, as used herein, refers tostraight chain alkyloxy groups of one to six carbon atoms.

The carboxylic groups herein are derived from the correspondingcarboxylic acids containing from 1 to 12 carbon atoms and possessstraight, branched, cyclic or cyclicaliphatic chain structure which maybe saturated, unsaturated, or aromatic and optionally substituted bygroups, such as hydroxy, alkoxy containing up to five carbon atoms,acyloxy containing up to six carbon atoms, nitro, amino, halogeno, andthe like. Typical esters thus include formate, acetate, propionate,enanthate, benzoate, trimethylacetate, t-butyl acetate, phenoxyacetate,cyclopentylpropionate, aminoacetate, B-chloropropionate, adamantoate,and the like, preferably a lower hydrocarbon carboxylic acyl group suchas acetyl, propionyl, butyryl, and the like, containing up to about sixcarbon atoms.

The addition of a methylene group to an unsaturated position of themolecule can be performed selectively at C-2,3 by the reaction of. anunsaturated compound with dimethylsulfoxonium methylide base [preparedin the manner of Corey et al., Journal of the American Chemical Society87, 1353 (1965)] in dimethylsulfoxide. Addition of the fused methylenegroup at the C-6,7 and C-l0,1l positions follows upon reaction of theunsaturated linkages with methylene iodide and a zinccopper couple inthe manner of Simmons and Smith, .1. Am. Chem. Soc. 81, 4256 (1959).Preferably, the addition of the methylene group is conducted on analiphatic hydrocarbon ester and thereafter the ester can be convertedinto the corresponding acid or alcohol by the procedures describedhereinabove to obtain methylene substituted aliphatic hydrocarbon acidsand methylene substituted aliphatic hydrocarbon alcohols. The thusobtained alcohol can then be etherified or esterified according toconventional etherification and esterification processes.

Similarly, the formation of the epoxide is selectively performed at theC-2,3position by reaction with hydrogen peroxide in aqueous alkalimedium, such as is usually provided by sodium hydroxide. Addition of theoxido group at the 06,7 and C-l0,l1 positions is performed withm-chloroperbenzoic acid, preferably in methylene chloride or chloroformsolution. The formation of an epoxide at C-2,3, C-6,7 and/or C-l0,l 1 inthe case of acids and alcohols is preferably accomplished via theappropriate or desired epoxidation of an aliphatic hydrocarbon ester andthen conversion of the ester into the acid or alcohol. If a methylenesubstituent and epoxide are to be introduced on the same backbone, it ispreferable to perform the methylene addition first and then carry outepoxidation.

A difluoromethylene group at positions C-6,7 and C-10,l1 of an aliphatichydrocarbon ester can be added by reacting the starting monoene, dieneor triene with about 1.2 molar equivalents of trimethyltrifluoromethyltin in the presence of sodium iodide in benzene/monoglyme solvent atreflux over a period of a few hours. By varying the mole ratio of thetwo reactants and the temperature and time of reaction, the reaction canbe favored toward one or the other 6,7 and 10,11 mono adducts and the6,7;l0,l1 bis adduct. The C-2,3 position is not attacked except underforcing conditions. Thereafter, the ester group can, if desired, beconverted into the corresponding acid or alcohol by the proceduresdescribed above.

ln the case of adding difluoromethylene to an aliphatic hydrocarbonalcohol, introduction at any one of positions C- 2,3; 06,7; and C-l0,llcan be accomplished by using about 1.2 molar equivalents oftrimethyltrifluoromethyl tin and sodium iodide in monoglyme andrefluxing for about 2 hours. Similarly, the bis adducts at C-2,3;6,7,C-2,3;10,1l and C- 6,7;10,l1 can be prepared by following the aboveprocedure with the exception of using about 2.5 molar equivalents oftrimethyltrifluoromethyl tin and sodium iodide and refluxing for about 3hours. Similarly, the tris adduct can be obtained by using about 5 to 10molar equivalents of the reagents and refluxing for about 5 to 15 hours.The mono, his and tris adducts are separable by preparative gas-liquidchromatography.

A fused dichloromethylene group is introduced into an aliphatichydrocarbon ester by reacting the C-6 or C-lO monoene; C-2,6, C-2,10 orC-6,10 diene; or C-2,6,l0 triene thereof with phenyldichlorobromomethylmercury in benzene at reflux for from one to five hours. The relativeyield of the C- 6,7 and C-l0,ll mono adducts and the C-6,7;10,11 bisadduct varies with the amount of mercury reagent and the reactionconditions employed. Generally, about or slightly more than one molarequivalent provides the mono adducts predominantly, the his adduct beingfavored by use of about 2.5 molar equivalents. The mono and his adductsare separable by gasliquid chromatography. These adducts can beconverted into the correspondingly substituted aliphatic hydrocarbonacids and alcohol via the procedure described above. In the case ofaliphatic hydrocarbon alcohol starting materials, dichloromethylene canbe added at C-2,3 in addition to the formation of bis adducts(C-2,3;6,7, C-2,3;l0,l1, C- 6,7;l0,ll) by following the methodsdescribed above for aliphatic hydrocarbon esters and thereafterseparating the adducts by gas-liquid chromatography. In addition, byusing about four to six molar equivalents of the mercury reagent andrefluxing for about 5 hours, the tris adduct can be obtained fromcorresponding 2,6,10- triene starting material.

A hydroxy, lower alkoxy, chloro, fluoro or bromo group at one or morepositions on the backbone as indicated by formulas XVI through XXVllIcan be introduced via a number of methods.

At the C-2,3-position, a monohydroxy substituent is introduced bytreating a 2,3-oxido substituted aliphatic hydrocarbon ester with a moleor less of lithium aluminum hydride under mild conditions such as attemperatures of from 0 C to about 30 C for a few minutes, e.g., about15-30 minutes to furnish the corresponding 1,3-diol and thecorresponding 2,3-oxido-1-o1. For the preparation of 3-Ol-l derivativesof aliphatic hydrocarbon esters and acids, a ketone of formula Vll aboveis subjected to Reformatsky reaction (see for example, US. Pat. No.3,031,481).

Etherification is thereafter conducted by methods known per se. Forexample, the hydroxy group can be treated with sodium hydride followedby an alkyl halide, such as ethyl bromide, to form the desired(lower)alkoxy group. 2- l-lalotetrahydropyran and 2-halotetrahydrofuranare utilized for the corresponding tetrahydropyran-Z-yl andtetrahydrofuran-Z-yl ethers. Acylation is likewise accomplished by knownchemical processes, such as through the use of an acid anhydride in thepresence of acid catalyst, for example, ptoluenesulfonic acid.

A 2,3-dihydroxy substitution can be accomplished by treating a 2,3-oxidosubstituted aliphatic hydrocarbon ester with 0.1 to 0.001 N perchloricacid in aqueous solution at room temperature for about 16 hours. A2-hydroxy-3-lower alkoxy (straight chain) can be formed by similarperchloric acid treatment in a lower straight chain alcohol solventmedium. Alternatively, the 2,3-oxido starting material can be analiphatic hydrocarbon acid or alcohol to furnish the corresponding C-2and C-3 substituted compounds.

A 2-hydroxy-3-chloro, fluoro or bromo substitution can be similarlyaccomplished by treating a 2,3-oxido substituted aliphatic hydrocarbonester/acid or alcohol with I-lCl, HF or I-lBr, respectively.

Each of the'C-6,7 and C-10,11 positions can be similarly substituted.Alternatively, monohydroxy substitution at C-7 and/or C-ll can becarried out by treating the unsaturated aliphatic hydrocarbon withaqueous formic acid as described more fully hereinafter. Thereafter,etherification or esterification can be carried out by the methodsdescribed above.

Monohalo (chloro, fluoro or bromo) substitution or introduction can beaccomplished by treating an unsaturated aliphatic hydrocarbon ester oracid with hydrogen halide. Selective introduction at C-ll is obtained bytreatment of the unsaturated compound with the appropriate hydrogenhalide in carbon tetrachloride or other halogenated hydrocarbon solventsof low dielectric constant. Introduction at C-7 and C- 7,11 is favoredby performing the reaction in diethyl ether or benzene. This halointroduction can be performed using as the starting material either a 6or 10 monene, 2,10-diene, 2,6- diene, 6,10 -diene or 2,6,l-trieneunsaturated aliphatic hydrocarbon ester, acid, or alcohol.

Dihalo (Cl, F or Br) introduction at C-10,ll or C-6,7 or

tetrahalo introduction at C-6,7,l0,l1 can be accomplished by treating anunsaturated aliphatic hydrocarbon ester, acid or alcohol with chlorine,fluorine or bromine in a chlorinated hydrocarbon solvent. A mixture ofthe dihalo and tetrahalo products is obtained which is separable bychromatography. The starting material can be either a monene, diene ortriene. The 2-ene is unaffected by the reaction except in the case ofaliphatic hydrocarbon alcohols in which case halo substitution at C-2and 03 also takes place.

The bishydroxy derivatives (Z"=Z =hydroxy and/or Z=Z =hydroxy) areprepared from the precursor epoxide (introduced as described above) withaqueous acid as set forth above. Similarly, the procedure given above inthe insertion of the 6(10)-hydroxy-7( 1 1 )-alkoxy and 6(10)-hydroxy-7(l l halo substituents analagously apply.

In the preparation of the 6(10)-bromoand 6(10)-chloro- 7(1l)-hydroxycompounds, the starting unsaturated compound is treated with theappropriate quantity of N-bromoor N-chlorosuccinimide in aqueous organicsolvent, such as dioxane. The 1 corresponding 7(l1)-alkoxy compounds aresimilarly prepared in the presence of dry alkanol solvent. Use ofhydrogen fluoride starting with the corresponding oxido compoundsaffords some of the 6(10)-fluoro-7(1l)-hydroxy derivatives. Treatmentthereof with acidified alkanol solution affords the corresponding(lower) alkoxy compounds.

In the practice of the above described elaborations on the compoundshereof, relative sensitivities of various groups to certain reactionconditions dictates the preference for a general pattern of reactionsequence. Thus, in accordance herewith, the methyleneation reaction isusually performed initially on the triene. As mentioned, this can bedone selectively.

Theremaining sites of elaboration are generally epoxidized as the nextstep. This is particularly true for epoxidations at C- 2,3 position forwhich it is preferred not to have present a halo substituent on thebackbone chain. However, since the acidic conditions required for theaddition of hydrogen halides cleave the epoxide, it is preferred toinsert the oxide after such reactions are performed unless, of course,the epoxide is required for the insertion of the hydroxy(alkoxy)-halobis substituents, and the like.

With the exception of the above proviso for the oxido group, the fusedhalomethylene groups are preferably introduced after the fused methyleneand oxido' groups are present since these reactions are compatible withthese groups.

After all desired elaboration is complete, hydrogenation of any of theunsubstituted double bonds is, if desired, carried out. lilalogenationin the instance of introducing a tertiary halo atom is preferablyconducted on the desired olefin isolated after hydrogenation.

Certain exceptions to the above general and preferred sequence exist;however, upon slight modification of the reactions according to thepurposes desired in the preparation of particular compounds embraced bythe present invention, chemical obstacles are overcome. Thesemodifications are, as a whole, obvious to one skilled in the art and/orapparent by the preparative procedures set forth in the examplescontained hereinafter.

Separation of the various geometric isomers can be performed at anyappropriate or convenient point in the overall process. An advantageousand particular synthetically valuable point at which isomers can beseparated by chromatography and the like is at the conclusion of eachstep of the backbone synthesis, that is, after preparing each of thecompounds represented by formulas (VIII), (IX), and (X). Anotheradvantageous point includes that just after the selective addition ofthe methylene group at C-2,3.

The novel substituted aliphatic hydrocarbon esters, acids and alcohols(including the esters and ethers of said alcohols) of the presentinvention are arthropod maturation inhibitors. They possess the abilityto inhibit the maturation of members of the phylum Arthropoda,particularly, insects, in the passage from metamorphic stage to the nextmetamorphic stage. Thus, in the case of insects passing from the embryostage to the larva stage, thence to the pupa stage, and thence to theadult stage, contact with an effective amount of a compound of thepresent invention, at any of the first three stages, inhibits passage tothe next developmental stage with the insect either repeating passagethrough its present stage or dying. Moreover, these compounds exhibitovidical properties with insects and are accordingly useful in combatingthem. These compounds are very potent and thus can be used at extremelylow levels, for example, from 10 to 10- g. and are thus ad vantageouslyadministered over large areas in quantities suitable for the estimatedinsect population. Generally the substances are liquids and for thepurposes herein described, they can be utilized in conjunction withliquid or solid carriers. Typical insects against which these compoundsare effective include mealworm, housefly, bollweevil, cornborer,mosquito, cockroach, moth, and the like.

Although not intending to be limited by any theoretical explanation, itappears that the effectiveness of these derivatives can be traced totheir ability to mimic the activity of certain so-called juvenilehormone" substances, such as those described in US. Pat. Ser. No.2,981,655 and Law et al. Proc. Nat. Acad. Sci. 55, 576 (1966). Becauseof the potency of the compounds of the present invention, they can beemployed at extremely low concentrations, as noted above, to obtainreproducible and predetermined levels of activity. Juvenile hormonesubstances have been referred to as growth hormone also. Juvenilehormone was identified as methyl 10,11-oxido-7-ethyl-3,l1-trimethyltrideca-2,6-dienoate using an extract of cecropiamoths by Roeller et al., Angew. Chem. internat. Edit. 6, 179 (Feb.,1967) and Chemical & Engineering News, 48-49 (Apr. 10, 1967). A secondjuvenile hormone from the same source has been identified as methyl 10,1l-oxido-3,7,1 1- trimethyltrideca-2,b-dienoate by Meyer et al., The Two.luvenile Hormones from the Cecropia Silk Moth, Zoology (Proc. N.A.S.)60, 853 (1968). In addition to the natural juvenile hormones and theunidentified mixture of Law et al. above, some synthetic terpenoids havebeen reported to exhibit juvenile hormone activity Bowers et al., LifeSciences (Oxford) 4, 2323 (1965) methyl 10,11-oxido-3,7,11-trimethyldodeca-Z,o-dienoate; Williams et al., Journal of InsectPhysiology 11, 569 (1965 BioScience 18, No. 8, 791 (Aug, 1968);Williams, Scientific American 217, No. l, 13 (July, 1967); Science 154,248 (Oct. 14, 1966); Romanuk et al., Proc. Nat. Acad. Sci. 57, 349 (Feb,1967) 7,11- dichloro of esters of farnesoic acid Canadian Pat. No.

795,805 (1968); Masner et al., Nature 219, 395 (July 27, 1968); US. Pat.No. 3,429,970 and 3,453,362 farnesene derivatives.

The compounds embraced by the terms "substituted Z is hydrogen, hydroxyand esters and ethers thereof,

aliphatic hydrocarbon ester,substituted aliphatic hydrocar- 5 bromo, h1fluoro or h k n together with Z'", is u bon acid," substituted aliphatichydrocarbon alcohol," formulas A, XVI through XXVllI and the examplesare represented by the following formulas in which R, R', R, R", R, Z ZZ, Z and Z are as defined hereinabove.

in which,

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro,fluoro, or, when taken together with Z, is a carbon-carbon double bondbetween C-l0,l1 or one of the groups and Z is hydrogen, hydroxy andesters and ethers thereof, bromo, chloro, fluoro, or, when takentogether with 2, is a carbon-carbon double bond between C-6,7 or one ofthe groups in which,

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro,fluoro, or, when taken together with Z, is a carbon-carbon double bondbetween 06,7 or one of the groups Z is hydrogen, hydroxy and esters andethers thereof, bromo, chloro, fluoro, or, when taken together with Z,is a carbon-carbon double bond between C-2,3 or one of the groupscarbon-carbon double bond between C-l0,ll or one of the groups OCh orCF2;

and V Z is hydrogen, hydroxy and esters and ethers thereof, bromo,chloro, fluoro, or, when taken together with Z, is a carbon-carbondouble bond between C-6,7 or one of the groups bromo, chloro, fluoro,or, when taken together with Z, is a carbon-carbon double bond betweenC-6,7 or one of the groups Z is hydrogen, hydroxy and esters and ethersthereof, bromo, chloro, fluoro, or, when taken together with Z, is acarbon-carbon double bond between C-2,3 or one of the groupsdiethylaminoacetate,

in which,

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro,fluoro, or, when taken together with Z, is a carbon-carbon double bondbetween C-10,l 1;

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro,fluoro, or, when taken together with Z", is a carbon-carbon double bondbetween C-6,7; and

Z is hydrogen, hydroxy and esters and ethers thereof, bromo, chloro,fluoro, or, when taken together with Z, is a carbon-carbon double bondbetween C-2,3, provided that at least one of Z, Z, Z, Z and Z is bromo,chloro or fluoro.

in which,

Z is hydrogen, hydroxy and esters and ethers thereof, or, when takentogether with Z, is a carbon-carbon double bond between C-2,3;

Z is hydrogen, or hydroxy and esters and ethers thereof;

Z is hydrogen, hydroxy and esters and ethers thereof, or, when takentogether with Z, is a carbon-carbon double bond between C-6,7;

Z is hydrogen or hydroxy and esters and ethers thereof; and

Z is hydrogen, hydroxy and esters and ethers thereof, or, when takentogether with Z, is a carbon-carbon double bond, provided that at leastone of Z Z, Z, Z and Z is hydroxy or the ester or ether thereof.

in which,

2*" is hydrogen; Z is hydrogen, or, when taken together with Z is acarbon-carbon double bond between 02,3; 2" is hydrogen; Z is hydrogen,or, when taken together with Z is a carbon-carbon double bond betweenC-6,7; 2 is hydrogen; and Z" is hydrogen, or, when taken together withZ'", is a carbon-carbon double bond between 010,1 1, provided that informula XL at least one of R, R or R is lower alkyl of at least twocarbon atoms.

The tenn "hydroxy and esters and ethers thereof, as used herein, refersto free hydroxyl and esters and ethers which are hydrolyzable to freehydroxyl. Typical esters are carboxylic esters of up to 12 carbon atomswhich are saturated or unsaturated and of straight chain aliphatic,branched chain aliphatic, and cyclic or cyclic aliphatic structure, suchas acetate, propionate, butyrate, valerate, caproate, enanthate,pelargonate, acrylate, undecanoate, phenoxyacetate, benzoate,phenylacetate, diethylacetate, trimethylacetate, trichloroacetate,t-butylacetate, trimethylhexanoate, methylneopentylacetate,cyclohexylacetate, cyclopentylpropionate, adamantoate, methoxyacetate,acetoxyacetate, aminoacetate,

B-chloropropionate, 2-chloro-4- nitrobenzoate, piperidinoacetate, andthe like, preferably a lower hydrocarbon carboxylic ester containing upto six carbon atoms. Typical ethers are formed by etherification of thehydroxy group by tetrahydrofuran-Z-yl, tetrahydropyran-2-yl or by amonovalent hydrocarbon group of up to eight carbon atoms which can be ofstraight, branched, cyclic or cyclic aliphatic structure, such as alkyl,alkenyl, cycloalkyl, or am!- kyl, e.g., methyl, ethyl, propyl, butyl,pentyl, butenyl, phenethyl, benzyl, cyclopentyl, cyclohexyl, and thelike.

The presence of at least one and optionally two double bonds in theforegoing compounds permits the existence of geometric isomerism in theconfiguration of these compounds. This isomerism occurs with regard tothe double bond bridging the C-2,3 carbon atoms, the C-6,7 atoms, and C-10,ll atoms. Obviously, isomerism at the C-l0,l I carbon atoms occursonly when R and R are different alkyl groups.

Thus, the isomers are the cis and trans of the monoene series and thecis,cis; cis,trans; trans,cis; and trans,trans of the diene series; eachof which isomers in each series being in cluded within the scope of thisinvention. Preferably, the isomerism relative to the double bond betweenC-2 and C-3 is trans. Each of these isomers are separable from thereaction mixture by which they are prepared by virtue of their differentphysical properties via conventional techniques, such as chromatography,including thin-layer and gas-liquid chromatography, and fractionaldistillation.

The following examples will serve to further typify the nature of thisinvention. In some instances, the various isomeric forms are specified;however, in any of the reaction steps, the carbon-carbon double bondscan be cis or trans independent of the other or, isomeric mixtures canbe employed.

EXAMPLE 1 Part A To a solution of 20.9 g. of the ethylene ketal ofl-bromo-4- pentanone (obtained by treating l-bromo-4-pentanone withethylene glycol in benzene in the presence of p-toluene-sulfonic acid)in ml. of benzene is added 20 g. of triphenylphosphine. This mixture isheated at reflux temperature for 2 hours and then filtered. The solidmaterial thus collected is washed with benzene, dried in vacuo, andadded to 6.49 g. of butyl lithium in 50 ml. of dimethylsulfoxide. Thismixture is stirred until an orange solution is obtained and 3.8 g. ofmethyl ethyl ketone is then added. This mixture is stirred at about 25 Cfor about 8 hours, poured into water, and this mixture is extracted withether. The ethereal extracts are concentrated and the residue thusobtained is added to a 0.1 N solution of hydrochloric acid in aqueousacetone and stirred for about 15 hours. The mixture is then poured intoice water and extracted with ethyl acetate. After washing these extractswith water and drying them over sodium sulfate, they are evaporated toyield a mixture of the cis and tans isomer of 6-methyl-5-octen-2-onewhich is separated by preparative gas-liquid chromatography into theindividual isomers.

Part B To a solution of 20.9 g. of the ethylene ketal of l-bromo-4-pentanone in 100 ml. of benzene is added 20 g. of triphenylphosphine.This mixture is heated at reflux temperature for 2 hours and thenfiltered. The solid material thus collected is washed with benzene,dried in vacuo, and added to 6.49 g. of butyl lithium in 50 ml. ofdimethylsulfoxide. This mixture is stirred until an orange solution isobtained and 5.5 g. of trans 6-methyl-5-octen-2-one (the ketone obtainedin Part A) is then added. This mixture is stirred at about 25 C forabout 8 hours, poured into water, and this mixture is extracted withether. The ethereal extracts are concentrated and the residue thusobtained is added to a (H N solution of hydrochloric acid in aqueousacetone and stirred for about 15 hours. The mixture is then poured intoice water and extracted with ethyl acetate. After washing these extractswith water and drying them over sodium sulfate, they are evaporated tofurnish a mixture of the trans, trans and cis, trans isomers of 6,10-dimethyldodeca-S,9-dien-2-one which is separated by preparativegas-liquid chromatography to the individual isomers.

By repeating the above procedure with the exception of using cis6-methyl-5-octen-2-one in place of trans 6-methyl-5- octen-2-one, thereis obtained a mixture of the cis, cis and trans, cis isomers of6,10-dimethyldodeca-S,9-dien-2-one which is separated as describedabove.

Similarly, in the above procedure, instead of using either the trans orcis isomers of 6-methyl-5-octen-2-one as the starting material, therecan be used a mixture of the isomers obtained in Part A in which case amixture of the four isomers is obtained which can then be separated bypreparative gas-liquid chromatography into the four isomers.

Part C A mixture of 11.2 g. of diethyl carbomethoxy methylphosphonate in100 ml. of diglyme is treated with 2.4 g. of sodium hydride. Thismixture is stirred until the evolution of gas ceases and 7.5 g. oftrans, trans 6,10-dimethyldodeca- 5,9-dien-2-one is then slowly addedwith stirring, maintaining a temperature below 30 C. The mixture isstirred for about 15 minutes and then diluted with water and extractedwith ether. These ethereal extracts are washed well with water, driedover sodium sulfate and evaporated to remove the solvent to furnish amixture of the trans,trans,trans and cis,trans,trans isomers of methyl3,7,11-trimethyltrideca-2,6,lO-trienoate which is separated bypreparative gas-liquid chromatography.

The above procedure is repeated with the exception of using cis,trans6,10-dimethyldodeca-5,9-dien-2-one as the starting material in place ofthe trans,trans isomer and there is obtained a mixture of thecis,cis,trans and trans,cis,trans isomers of methyl 3,7,11-trimethyltrideca-2,6,lO-trienoate.

Similarly, in the above procedure, in place of using either thetrans,trans or cis,trans isomer of 6,10-dimethyldodeca- 5,9-dien-2-oneas the starting material, there can be used as the starting material amixture of isomers obtained in Part B and thereafter separating theindividual isomers by preparative gas-liquid chromatography.

In the examples which follow, in some instances the isomeric forms arenot specified; however, in each of the procedures set forth in thefollowing examples, reference to the compound or compounds named isinclusive of each isomer or isomeric mixtures thereof. In other words,the following examples are illustrative of procedures which areapplicable to compounds embracing individual isomers or isomericmixtures of the type set forth hereinabove.

EXAMPLE 2 By repeating the process of Example 1 with the exceptions thatin Part A thereof, methyl ethyl ketone is replaced with the ketoneslisted in column I and the ketone thus obtained is used in place of6-methyl-5-octen-2-one in Part B, there is obtained the acid esterslisted in column 11.

acetone methyl n-propyl ketone diethyl ketone methyl i-propyl ketonemethyl n-butyl ketone ethyl n-propyl ketone methyl t-butyl ketone methyli butyl ketone methyl s-butyl ketone ethyl i-propyl ketone methyl n-amylketone ethyl n-butyl ketone 3-ethy1-2- pentanone diisopropyl ketonemethyl n-hexyl ketone S-ethyl-3- heptanone II methyl3,7,l1-trimethyldodeca-2,6,10-trienoate methyl 3,7,1l-trimethyltetradeca-2,6,10-trienoate methyl 3,7-dimethy1-1l-ethyltrideca-2,6,10-trienoate methyl3,7,11,12-tetramethyltrideca-2,6,10-trienoate methyl 3,7,1l-trimethylpentadeca-2,6,l-trienoate methyl 3,7-dimethyl-ll-ethyltetradeca-2,6,10-trienoate methyl3,7,11,12,12-pentamethyltrideca-2,6,l0- trienoate methyl3,7,11,13-tetramethyltetradeca-2,6,10-trienoate methyl3,7,11,12-tetramethyltetradeca-2,6,l0-trienoate methyl3,7,12-trimethyl-1lethyltrideca-2,6,IO-trienoate methyl3,7,11-trimethylhexa' deca-2,6,l0-trienoate methyl 3,7-dimethyl-ll-ethylpentadeca-2,6,lO-trienoate methyl 3,7,1l-trimethyl-l2-ethyltetradeca-2,6, 1 0- trienoate methyl 3,7,l2-trimethyl-l l-(i-propyl)-trideca-2,6,10- trienoate methyl 3,7,1l-trimethylheptadeca'2,6,10-trienoate methyl 3,7-dimethyl-11,13-diethyltetradeca-2,6,l0- trienoate 4-deeanone methyl3,7-dimethyl-1l-(npropyl)-heptadeca-2,6,l0- trienoate di-n-amyl methyl3,7-dimethyl-l1-(nketone amyl)-hexadeca-2,6,10-

trienoate di-n-hexyl methyl 3,7-dimethyl-11-(nketonehexyl)-heptadeca-2,6,l0-

trienoate EXAMPLE 3 The process of Example 1 is repeated with theexception that in Part A thereof, l-bromo-4-pentanone is replaced withthe l-bromo-4-ketones listed in Column III to furnish the acid esterslisted in Column IV.

l-bromo-4- methyl 3,1l-dimethyl-7-ethy1- hexanonetrideca-2,6,10-trienoate l-bromo-4- methyl 3,11-dimethyl-7-(nheptanonepropyl)-trideca-2,6,l0-

trienoate l-bromo-4 methyl 3,11-dimethy17-(noctanonebutyl)-trideca-2,6,10-

trienoate l-bromotmethyl 3,11-dimethyl-7-(nnonanoneamyl)-trideca-2,6,l0-

trienoate methyl 3,11-dimethyl-7-(ipropyl)trideca 2,6,10- trienoatemethyl 3,1l-dimethyl-7-(ibutyl)-trideca-2,6,10- trienoate methyl3,1l-dimethyl-7-(tbutyl)-trideca-2,6,10- trienoate 1-bromo-5-methyl4-hexanone l-bromo-6-methyl -heptanone l-bromo-5,5-dimethyl 4-hexanonemethyl 3,1 l-dimethyl-7-(n-propyl)-tetradeca-2,6,l0- trienoate,

methyl 3 ,1 1-dimethyl-7-(n-butyl)-tetradeca-2,6,10- trienoate,

methyl 3 ,1 1-dimethyl-7-(n-amyl )-tetradeca-2,6 l 0- trienoate,

methyl 3 ,1l-dimethyl-7-(i-propyl)-tetradeca-2,6 ,10- trienoate,

methyl 3,1 1-dimethyl-7-(i-butyl)-tetradeca-2,6,l0- trienoate,

methyl 3 ,1 1-dimethyl-7-(t-butyl)-tetradeca-2,6, l0- trienoate,

methyl 3-methyl-7,l l-diethyltrideca-2,6,10-trienoate,

methyl 3-methyl-7-(n-propyl)-l1-ethyltrideca-2,6 ,10- trienoate,

methyl 3.-methyl-7-( n-butyl )-l l-ethyltrideca-2,6,10- trienoate,

methyl 3-methy1-7-(n-amy1)-1 l-ethy1trideca-2,6,l0- trienoate,

methyl 3-methyl-7-( i-propyl )-l 1-ethyltrideca-2,6 ,10- trienoate,

methyl 3-methyl-7-(i-butyl)-l 1-ethy1trideca-2,6,l0- trienoate,

methyl 3 -methyl-7-(t-butyl )-1 1-ethyltrideca-2,6 l 0- trienoate,

methyl 7-ethyl'3 ,1 1 ,l2-trimethyltrideca-2,6,10-trien0ate,

methyl 7-(n-propy1 )-3 ,1 1,1 2-trimethyltrideca-2,6,10- trienoate,

methyl 7-(n-butyl )-3,1 1,12-trimethyltricleca-2,6,10- trienoate,

methyl 7-(i-propyl)-3-3-ethyll1-methyltetradeca-2,6,l0- trienoate,

methyl 7-(i-butyl)-3-ethyl-1 lmethyltetradeca-2,6,ltrienoate,

methyl 7-(tbutyl)-3-ethyl-l l-methyltetradeca-2,6, l 0- trienoate,

methyl 3,7,1 1-triethyltrideca-2,6,10-trienoate,

methyl 7-(n-propyl)-3,1 l-diethyltrideca-2,6,IO-trienoate, methyl7-(n-butyl)-3,1 1-diethyltrideca-2,6,IO-trienoate, meth yl 7-( n-amyl)-3,1 1-diethyltrideca-2,6 1 O-trienoate, methyl 7-(i-propyl)-3,l1-diethyltrideca-2,6,lO-trienoate, methyl 7-( i-butyl )-3 ,11-diethyltrideca-2,6,10-trienoate, methyl 7-( t-butyl )-3,11-diethyltrideca-2,6, 1 O-trienoate, methyl 3 ,7 -diethyl-1l-methylpentadeca-2,6,10-trienoate,

methyl 7-(n-propyl)-3 -ethyl-1 1-methylpentadeca-2,6, l 0- trienoate,

methyl 7-(n-butyl )-3 -ethyl-1 1-methylpentadeca-2,6, l 0- trienoate,

methyl 7-( n-amyl)-3 -ethyl-1 1 -methylpentadeca-2,6,10- trienoate,

methyl 7-(i-propyl)-3-ethyl-l 1 -methylpentadeca-2,6,10- trienoate,

methyl 7-(i-butyl)-3 -ethyl-l l-methylpentadeca-2,6,10- trienoate,

methyl 7-(t-butyl)-3-ethyl-1l-methylpentadeca-2,6,l0- trienoate,

methyl 3,7,11-triethyltetradeca-2,6,10-trienoate, methyl 7-(n-propyl)-3,1 1-diethyltetradeca-2,6,10- trienoate,

methyl 7-(n-butyl)-3,1 1-diethyltetradeca-2,6,l0-trienoate, methyl7-(n-amyl )-3,1 l-diethyltetradeca2,6,10-trienoate, methyl7-(i-propyl)-3,l 1-diethyltetradeca-2,6,IO-trienoate, methyl 7-( i-butyl)-3 ,1 1-diethyltetradeca-2,6,10-trienoate, methyl 7-(t-butyl)-3,11-diethyltetradeca-2,6,IO-trienoate,

methyl 3,7 -diethyl-l 1,12,12-trimethyltrideca-2,6,10- trienoate,

methyl 7-(n-propyl)-3-ethyl-l 1,12,12-trimethyltrideca-2,6,l0-trienoate, and the like.

EXAMPLE 5 The procedure of Example 1 is repeated with the exception thatin Part C, diethyl carbomethoxy methyl phosphonate is replaced withother dialkyl carboalkoxy methyl phosphonates, e.g. diethyl carbethoxymethyl phosphonate, diethyl n-propoxycarbonyl methyl phosphonate,dimethyl n-butoxycarbonyl methyl phosphonate, and the like, to furnishthe corresponding alkyl 3,7,11-trimethyltrideca-2,6,lO-trienoate, e.g.ethyl 3,7,1 1-trimethyltrideca-2,6,IO-trienoate, n-propyltrimethyltrideca-2,6,lo-trienoate, n-butyl 3,7,11-trimethyltrideca- 1,6,l0-trienoate, and the like.

Similarly, by repeating the procedure of Examples 2, 3 and 4 with theexception that diethyl carbomethoxy methyl phosphonate is replaced withdiethyl carbethoxy methyl phosphonate, diethyl n-propoxycarbonyl methylphosphonate and dimethyl n-butoxycarbonyl methyl phosphonate, thecorresponding ethyl 2,6,10-trienoates, n-propyl 2,6, l O-trienoates andn-butyl 2,6, l O-trienoates are obtained. For example,

ethyl 3,7,1 1-trimethyldodeca2,6,IO-trienoate,

n-propyl 3,7,1 1-trimethyldodeca-2,6,lO-trienoate,

n-butyl 3 ,7,1 1-trimethyldodeca-2,6, l O-trienoate,

ethyl 3 ,1 1-dimethyl-7-ethyltrideca-2,6, l O-trienoate,

n-propyl 3,1 1-dimethyl-7-ethyltrideca-2,6,IO-trienoate, nbutyl 3 ,11-dimethyl-7-ethy1trideca-2,6, 1 O-tn'enoate,

ethyl 3,1 l-dimethyl-7-ethyldodeca-2,6,10-trienoate,

n-propyl 3 ,11-dimethyl-7-ethyldodeca-2,6,lo trienoate,

n-butyl 3 ,1 l-dimethyl-7-ethyldodeca-2,6,10-trienoate,

ethyl 3-ethyl-7 ,1 1-dimethy1trideca-2,6, l O-trienoate,

n-propyl 3-ethyl-7,l 1-dimethyltrideca-2,6,lO-trienoate,

n-butyl 3-ethyl-7,l 1 -dimethyltrideca-2,6,10-trienoate,

ethyl 3-ethyl-7,1 l-dimethyldodeca-2,6,IO-trienoate,

n-propyl 3-ethy|-7,l 1-dimethyldodeca-2,6,l0-trienoate,

n-hutyl 3-ethyl7.l l-dimethyldodeca-2,6,IO-trienoate, ethyl.lfi-diothyhl l-methyltrideca-2,6,IO-trienoate,

22 n-propyl 3,7-diethyl-1 1-methyltrideca-2,6,10-trienoate, n-butyl3,7-diethyl-11-methyltrideca-2,6,IO-trienoate, and the like.

EXAMPLE 6 A mixture of 1 g. of methyl 3,7,11-trimethyltrideca-2,6,l0-trienoate, 60 ml. of methanol, 0.1 g. of sodium carbonate, and 6 ml. ofwater is heated as reflux for 2 hours. The mixture is then cooled,diluted with water and extracted with ether. The ethereal extracts arewashed with water, dried over sodium sulfate and evaporated to removethe solvent. The residue is subjected to fractional vacuum distillationto yield 3,7,11- trimethyltrideca-2,6, 1 O-trienoic acid.

By repeating the procedure of this example with the exception ofsubstituting the other acid esters, preferably the methyl esters orethyl esters obtained by the above procedures (Examples 2, 3, 4 and 5)for methyl 3,7,1 l-trimethyltrideca- 2,6,10-trienoate, there is obtainedthe corresponding free acids, e.g.3,7,11-trimethyldodeca-2,6,IO-trienoic acid, 3,11-dimethy1-7-ethyltrideca-2,6,10-trienoic acid, 3,7-diethyl-1lmethyltrideca-2,6,IO-trienoic acid, 3,1 l-dimethyl-7-ethyldodeca-2,6,10-trienoic acid, 7,11-dimethyl-3-ethyltrideca- 2,6,10-trienoic acid, 7,11-dimethyl-3-ethyldodeca-2,6,10- trienoic acid, and the like.

EXAMPLE 7 A suspension of 0.5 g. of 5 percent palladium-on-carboncatalyst in 50 ml. of benzene is hydrogenated for 30 minutes. A solutionof 2 g. of 6,10-dimethyldodeca-S,9-dien-2-one in ml. of benzene is addedand hydrogenated with agitation until the theoretical amount of hydrogenhas been absorbed. The catalyst is thereafter removed by filtration andthe solution is evaporated to yield 6,10-dimethyldodec-S-en-2-one,6,10-dimethyldodec-9-en-2-one and 6,10-dimethyldodecan-2- one which areseparated and purified by preparative gas-liquid chromatography.

EXAMPLE 8 By repeating the procedure of Part A of Example 1 using, forexample, the ketones listed in Column V in lieu of methyl ethyl ketoneand using the ketone thus obtained for the procedure of Part B ofExample 1, there are obtained the respective products listed in ColumnV1 which are hydrogenated using the procedure of Example 7 to afford6,10-dimethylundec-5-en-2-one, 6,10-dimethylundec-9-en-2 one, and6,10-dimethylundecan-Z-one; 6-methyl-10-ethyldodec-5-en-2-one,6-methyl-10-ethyldodec-9-en-2-one, and 6-methyl-10-ethyldodecan-2-one;6,10,1 1-trimethyldodec-5 en-2-one, 6,10,1 1-trimethyldodec-9-en-2-one,and 6,10,11- trimethyldodecan-Z-one; 6-methy1-10-ethyltridec-5-en-2-one,6 methyl -l0-ethyltridec-9-en-2-one, and6-methyl-10-ethyltridecan-2-one; and 6,10,11,1l-tetramethyldodec-S-en-Z- one, 6,10,1 1,1 1-tetramethyldodec-9-en-2-one, and 6,10,11,1 l-tetramethyldodecan-Z-one, respectively.

acetone 6,10-dimethylundeca-S,9-dien- 2-one diethyl ketone6-methyl-l0-ethyldodeca5,9-

dien-2-c ne methyl i-propyl 6,l0,l1-trimethyldodeca-S,9-

ketone dien-Z-one ethyl n-propyl G-methyll 0-ethyltrideca-5,9-

ketone dien-Z-one methyl t-butyl 6,l0,l 1,1 l-tetramethyldodeca ketone 5,9-dien-2-one By repeating the procedure of Part C of Example 1 usingdiethyl carbethoxymethyl phosphonate in place of diethylcarbomethoxymethyl phosphonate and using the mono-unsaturated andsaturated 2-ketones prepared in this example in place of6,10-dimethyldodeca-S,9-dien-2-one, the following ethyl esters areobtained:

ethyl 3,7,1 l-trimethyldodeca-2,6-dienoate,

ethyl 3,7,1l-trimethyldodeca-2,10-dienoate,

ethyl 3,7,1 l-trimethyldodec-Z-euoate,

.33, ethyl 3,7-dimethyl1 l-ethyltrideca2,6-dienoate, ethyl 3 ,7-dimethyl-1 l-ethyltrideca-Z, l O-dienoate, ethyl 3 ,7 -dimethyl-llethyltridec-2-enoate, ethyl 3,7,1 1,1Z-tetramethyltrideca-Z,6-dienoate,ethyl 3,7,1 1,l2-tetramethyltrideca-2,IO-dienoate, ethyl 3,7,11,1Z-tetramethyltridec-Z-enoate, ethyl 3 ,7 -dirnethyl-11-ethyltetradeca-2,6-dienoate ethyl 3 ,7-dimethyl-l l-ethyltetradeca-2,l O-dienoate, ethyl 3 ,7-dimethyl-l l-ethyltetradec-2-enoate, ethyl 3 ,7,1 1,12 ,1 Z-pentamethyltrideca-Z ,6-dienoate, ethyl 3,7 ,11,l2,12-pentamethyltrideca-2,10-dienoate, and ethyl 3 ,7 ,11,l2,1Z-pentamethyltridec-Z-enoate, respective- EXAMPLE 9 By repeatingthe procedure of Part A of Example 1 using the l-bromo-4-alkanoneslisted in Column VII in place of 1- bromo-4-pentanone, the correspondingketones listed in Column Vlll are obtained which are used in Part B ofExample 1 to afford the diunsaturated ketones listed in Column 1X. The

' diunsaturated ketones are hydrogenated using the procedure of Example7 to yield 6-ethyl-l0-methyldodec-5-en-2-one, 6-ethyl-10-methyldodec-9-en-2-one, and 6-ethyl-10-rnethyldodecan-Z-one;6-(n-propyl)-1O-methyldodec-S-en-2 one, 6-(n-propyl)-lO-methyldodec-Q-en-Z-one, and 6-(n-propy1)-l0-methyldodecan-Z-one; 6-(i-propyl)-10-methyldodec-5-en-2- one,6-(i-propyl)-l0-methyldodec-9-en-2-one, and6-(ipropyl)-l-methyldodecan-2-one; and6-(t-butyl)-l0-methyldodec-S-en-Z-one,6-(t-butyl)-10-methyldodec-Sl-en-2-one, and 6-(t-butyl)- lO-methyldodecan-Z-one, respectively.

Vll l-bromo-4-hexanone Vlll 7-methylnon-6-en- 3one l-bromo-4-heptanone8-methyldec-7-en- 4-one l-bromo-5-methyl-4- 2,7-dimethylnon-6- hexanoneen-3-one methyldodeca-S ,9-

dien-Z-one l-bromo-S ,S-di- 2,2,7-trimethylnon- 6-( t-butyl)-l0- methyl-4-hexanone 6-en-3-one methyldodeca-5,9-

EXAMPLE By using the ketones listed in Column Vlll in place of 6-methyl-Smcten-Z-one and the ethylene ketal of the l-bromo- 4-alkanoneslisted in Column VII in place of the ethylene ketal ofl-bromo-4-pentanone in Part B of Example 1, there is obtained 7-ethyl-ll-methyltrideca-6,l0-dien-3-one,

8-(n-propyl)- l 2-methyltetradeca-7,l l-dienA-one,

2,1 l-dimethyl-7-(i-propyl)trideca-6,l0-dien-3-one, and

2,2,1 l-trimethyl-7-(t-butyl)-trideca-6,10-dien-3-one, respectively,which are hydrogenated using the procedure of Example 7 to yield7-ethyl-1 l-methyltridec--en-B-one,

7-ethyl-l 1 -methyltriclec-l 0-en-3 -one, and

7-ethyl-l 1 -methyltridecan-3-one;

8-(n-propyl)-12-methyltetradec-7-en-4-one,

8-(n-propyl l Z-methyltetradec-l l-en-4-one, and

8-(n-propyl)-l2-methyltetradecan-4-one;

2,1 1-dimethyl-7-(i-propyl)-tridec-6-en-3-one,

2,1 1-dimethyl-7-(i-propyl)-tridec-l0-en-3-one, and

2,1 l-dirnethyl-7-(i-propyl)-tridecan-3-one; and

2,2,1 1-trimethyl-7-(t-butyl)-tridec-6-en-3-one,

2,2,1 1-trimethyl-7-(t-butyl)-tridec-10-en-3-one, and

2,2,1 l-trimethyl-7-(t-butyl )-tridecan-3 -one, respectively.

The thus-obtained mono-unsaturated ketones and saturated ketones aresubjected to the procedure of Part C of Example 1 using diethylcarbethoxymethyl phosphonate to obtain the following ethyl esters:

ethyl 3,7-diethyl-l 1-methyltrideca-2,6-dienoate,

ethyl 3 ,7-diethyl- 1 l-methyltrideca2, l O-dienoate,

ethyl 3 ,7 -diethyl-l l-methyltridec-Z-enoate,

ethyl 3,7-(n-propyl)-1 l-methyltrideca-2,-dienoate,

ethyl 3 ,7 -(n-propyl )-1 l-methyltrideca-2, 1 O-dienoate,

ethyl 3 ,7-(n-propyl )-1 l-rnethyltridec-Z-enoate,

ethyl 3,7-di(i-propyl)-1 l-methyltrideca-2,6-dienoate,

ethyl 3,7-di(i-propyl)-l l-methyltrideca-2, 1 O-dienoate,

ethyl 3 ,7-di(i-propyl)-1 l-methyltridec-2-enoate,

ethyl 3,7-di( t-butyl )-l l-methyltrideca-2,o-dienoate,

ethyl 3 ,7-di(t-butyl )-1 1-methyltrideca-2, l O-dienoate, and

ethyl 3,7-di(t-butyl)-l l-methyltridec-2enoate, respectively.

EXAMPLE 1 1 X1 6-ethyll q-methyluncleca-fifl dien-Z-one tS-(n-propyl)-10-methylundeca- 5 ,9-dien-2-one 6-(i-propyl)-l(Lmethylundeca- 5,9-dien-2-one 6-(t-butyl)-lO-methylundeca- 5,9-dien-2-one X 7-methyloct-fi-en-3 -one B-m ethylnon-7-en-4-one2,7-dirnethyloct-6-en-3-one 2,2,7-trimethyloet-6-en'3-one The compoundslisted in Column X1 are hydrogenated ac cording to the procedure ofExample 7 to yield 6-ethyl-10- methylundec-S-en-Z-one,6-ethyl-10-methylundec-Q-en-Z-one and 6-ethyl-IO-methylundecan-Z-one;6-(n-propyl)- 10- methylundec-S-en-Z-one, 6-(n-propyl)-l0-methylundec-9-en- 2-one and6-(n-propyl)-lO-methylundecanZ-Qne;6-(ipropyl)-10-methylundec-S-en-2-one, 6-(i-propyl l 0-methylundec-9-en-2-one and 6-(i-propyl)-lO-methylundecan- 2-one; and6-(t-butyl)-l0-methylundec-5-en-2one,6-(t-butyl)-10-methlundec-9-en-2-one and6-(t-butyl)-l0-methylundecan-Z-one, respectively.

The thus-obtained mono-unsaturated and saturated ketones are treatedwith diethyl carbethoxymethylphosphonate using the procedure of Example1 (Part C) to afford:

ethyl 3,1 1-dirnethyl-7-ethyldodeca-2,6-dienoate,

ethyl 3,1 l-dimethyl-7-ethyldodeca-2,10-dienoate,

ethyl 3,1 l-dimethyl-7-ethyldodec-2-enoate,

ethyl 3,1 l-dimethyl-7-(n-propyl)-dodeca-2,o-dienoate,

ethyl 3 ,1 1 -dimethyl-7-(n-propyl )-dodeca-2, l O-dienoate,

ethyl 3,1 l-dimethyl-7-(n-propyl)-dodec-2-enoate,

ethyl 3,1 l-dimethyl-7-(i-propyl)-dodeca-2,6-dienoate,

ethyl 3,1 l-dimethyl-7-(i-propyl)-dodeca-2,lO-dienoate,

ethyl 3,1 l-dimethyl-7-(i-propyl)-dodec-2enoate,

ethyl 3,1 1-dimethyl-7-(t-butyl)-dodeca-2,6-dienoate, ethyl 3,11dimethyl-7-(t-butyl)-dodeca-2,IO-dienoate, and

ethyl 3,1 1-dimethyl-7-(t-butyl)-dodec-2-enoate, respectively.

EXAMPLE 12 The mono-unsaturated ketones listed in Column X aresubstituted in place of 6-methyl-5-octen-2-one and the ethylene ketal ofthe 1-bromo-4-hexanone is used in place of the ethylene ketal of1-bromo-4-pentanone in the process of Example 1 (Part B) to give7-ethyl-l1-methyldodeca-6,10-dien- 3-one,7-(n-propyl)-11-methyldodeca-6,lO-dien-3-one,7-(ipropyl)-l1-methyldodeca-6,10-dien-3-one and 7-(t-butyl)-1l-methyldodeca-6,10-dien-3-one, respectively, which are hydrogenatedusing the procedure of Example 7 to yield 7- ethyl-l1-methyldodec-6-en-3-one, 7-ethyl-11-methyldodecl-en-3one and7-ethyl-1l-methyldodecan-3-one; 7-(npropyl)-l l-methyldodec-6-en-3-one,7-(n-propyl)-1 l-rnethyldodec-l0-en-3-one and7-(n-propyl)-1l-methyldodecan-3- one;7-(i-propyl)-1lmethyldodec6-en-3-one, 7-(i-propyl)-1l-methyldodec-10-en-3-one and 7-(i-propyl)-1l-methyldodecan-3-one; and7-(t-butyl)-11-methyldodec-6-en-3-one, 7-(t-buty1)-l1-methyldodec-10-en-3-one and 7-(t-butyl)-11- methyldodecan-3-one,respectively.

The thus-obtained mono-unsaturated and saturated 3- ketones are treatedwith diethyl carbethoxymethylphosphonate using the procedure of Example1 (Part C) to give:

ethyl 3,7-diethyl-11-methyldodeca-2,6-dienoate,

ethyl 3,7-diethyl-l l-rnethyldodeca-2,10-dienoate,

ethyl 3,7-diethyl-1 l-methyldodec-Z-enoate,

ethyl 3-ethyl-7-(n-propyl)-1 l-rnethyldodeca-2,6-dienoate,

ethyl 3-ethyl-7-(n-propyl)-1 1-methyldodeca-2,10-dienoate,

ethyl 3-ethyl-7-(n-propyl)-l 1-methyldodec-2-enoate,

ethyl 3-ethyl-7-(i-propyl)-l 1-methy1dodeca-2,6-dienoate,

ethyl 3-ethyl-7-(i-propyl)-l 1-methyldodeca-2,10-dienoate,

ethyl 3-ethyl-7-(i-propyl)-1 1-methyldodec-2-enoate,

ethyl 3-ethyl-7-(t-butyl)-l1-rnethyldodeca-2,6-dienoate,

ethyl 3-ethyl-7-(t-butyl)-11-methyldodeca-2,IO-dienoate, and

ethyl 3-ethyl-7-(t-butyl)-1 l-methyldodec-Z-enoate, respectively.

By repeating the procedure of this example using the ethylene ketal ofthe other l-bromo-4-alkanones listed in Column VII in place of theethylene ketal of l-bromo-4-hexanone, the corresponding 3-(n-propyl)-,3-(i-propyl)-, and 3- (t-butyl)-ethyl esters of the 3-ethyl estersenumerated in the preceding paragraph are obtained, for example, ethyl3-(npropyl)-7-ethyl-11-methyldodeca-Z,6-dienoate, ethyl3-(npropyl)-7-ethyl-1l-methyldodeca-Z,IO-dienoate and ethyl 3-(n-propyl)-7-ethy1-l 1-methyldodec-2-enoate.

EXAMPLE 13 The procedure of Example 1 (Part A) is repeated using diethylketone in place of methyl ethyl ketone and l-bromothexanone in place ofl-bromoi-pentanone to give 7-ethylnon-6-en-3-one. 13y repeating thisprocedure using ethyl ipropyl ketone, ethyl n-propyl lcetone, ethylt-butyl ketone,

- ethyl n-butyl ketone, and di-i-propyl lcetone in place of diethylhydrogenated using the procedure of Example 7 to yield 7,11-diethyltridec-6-en-3-one, 7,11-diethyltridec-10-en-3-one and 7,11-diethyltridecan-3-one; 1 1-(i-propyl)-7-ethyltridec-6-en- 3-one,ll-(i-propyl)-7-ethyltridec-l0-en-3-one andll-(ipropyl)-7-ethyltridecan-3-one; 7,1l-diethyltetradec-6-en-3- one,7,1l-diethyltetradec-10-en-3-one and 7,11-diethyltetradecan-S-one;1l-(t-butyl)-7-ethyltridec-6-en-3-one, 11-(t-butyl)-7-ethyltridec-l0-en-3-one and1l-(t-butyl)-7-ethyltridecan-3-one; 7,11-diethylpentadec-6-en-3-one,7,11- diethylpentadec-l 0-en-3-one and 7,1 l-diethylpentadecan-3- one;and 7 -ethyl-11-(i-propyl)-12-methyltridec-6-en-3-one, 7-ethyl-11-(i-propyl)-12-methyltridec-10-en-3-one and 7- ethyl-l1-(i-pr0pyl)-12-methyltridecan-3-one, respectively, each of which aretreated with diethyl carbethoxymethylphosphonate using the procedure ofExample 1 (Part C)to afford:

ethyl 3,7,1 1-triethyltrideca-2,6-dienoate,

ethyl 3,7,1 l-triethyltrideca-2,10-dienoate,

ethyl 3 ,7,1 1-triethyltridec-2-enoate,

ethyl 3,7,1 1-triethyl-lZ-methyltrideca-Z,6-dienoate,

ethyl 3,7,1 l-triethyl-l2-methyltrideca-2,10-dienoate,

ethyl 3,7 ,1 l-triethyll Z-methyltridec-Z-enoate,

ethyl 3,7,1 1-triethyltetradeca-2,6-dienoate,

ethyl 3 ,7,1 l-triethyltetradeca-2, l O-dienoate,

ethyl 3,7,1 l-triethyltetradec-2-enoate,

ethyl 3,7,1l-triethyl-l2,lZ-dimethyltrideca-Z,6-dienoate,

ethyl 3,7,11-triethyl-l2,12-dimethyltrideca-2,10-dienoate,

ethyl 3,7,1 1-triethyl-12, l 2-dimethyltridec-Z-enoate,

ethyl 3,7,1 1-triethylpentadeca-2,-dienoate,

ethyl 3 ,7,1 1-triethylpentadeca-2,10-dienoate,

ethyl 3,7,1 1-triethylpentadec-Z-enoate,

ethyl 3,7-diethyl-1 l-(i-propyl)- l 2-rnethyltrideca-2,6- dienoate,

ethyl 3,7-diethyl-1 1-( i-propyl)-l2-methyltrideca-2,10- dienoate, and

ethyl 3 ,7-diethyl-1 1-(i-propyl)-1Z-methyltridec-Z-enoate,respectively.

EXAMPLE 14 Each of 6,10-dimethyldodec-5-en-2-one,6,10-dimethyldodec-9-en-2-one and 6,10-dimethyldodecan-Z-one is treatedwith diethyl carbethoxyrnethylphosphonatc using the procedure of Example1 (Part C) to yield ethyl 3,7,11- trimethyltrideca-Z,6-dienoate, ethyl3,7,1 l-trirnethyltrideca- 2,10-dienoate and ethyl3,7,11-trimethyltridec-2-enoate, respectively.

EXAMPLE 15 A solution of 20.9 g. of the ethylene ketal of methyl 3-bromopropyl ketone (obtained by treating the ketone with ethylene glycolin benzene in the presence of p-toluenesulfonic acid) in ml. of benzeneis treated with 20 g. of triphenylphosphine. This mixture is heated atreflux temperatures for 2 hours and then filtered. The solid materialthus collected is washed with benzene, dried in vacuo and added to 6.49g. of butyl lithium in 50 ml. of dimethylsulfoxide. This mixture isstirred until a red solution is obtained and 7.2 g. of-hydroxy--methylheptan-2-one are then added. This mixture is stirred atabout 25 C for 8 hours, poured into water, and this mixture is extractedwith ether. The ethereal extracts are concentrated and the residue thusobtained is added to a 0.1 N solution of hydrochloric acid in aqueousacetone and stirred for 15 hours. The mixture is then poured into icewater and extracted with ethyl acetate. After washing these extractswith water and drying them over sodium sulfate, they are evaporated toyield a mixture of cis and trans 10-hydroxy-10- methylundec-S-en'Z-onewhich may be separated by fractional vacuum distillation or bypreparative gas-liquid chromatography.

A mixture of 11.2 g. of diethyl carbethoxymethylphosphonate in 100 ml.of diglyme is treated with 2.4 g. of sodium hydride. This mixture isstirred until the evolution of gas ceases and 7.5 g. of translO-hydroxy-lO-methylundec-S temperature below 30 C. The mixture isstirred for 15 minutes and then diluted with water and extracted withether. These ethereal extracts are washed well with water, dried oversodium sulfate and evaporated to remove the solvent. The residue issubjected to fractional vacuum distillation to yield cis, trans ethyl3,7,11-trirnethyl-11-hydroxydrodeca-2,6- dienoate and trans, transethyl3,7,11-trimethy1-ll-hydroxydodeca-2,6-dienoate.

By employing the cis isomer of lhydroxy-l0-methylundec--en-2-one in theforegoing procedure, there is obtained cis, cis ethyl 3,7,11-trimethyl-l1-hydroxydodeca-2,o-dienoate and trans, cis ethyl 3,7,1l-trimethyl-l1-hydroxydodeca-2,6- dienoate.

EXAMPLE 16 A solution of 20.9 g. of the ethylene ketal of methyl 3-bromopropyl ketone (obtained by treating the ketone with v ethyleneglycol in benzene in the presence of p-toluenesulfonic acid) in 100 ml.of benzene is treated with 20 g. of triphenylphosphine. This mixture isheated at reflux temperatures for 2 hours and then filtered. The solidmaterial thus collected is washed with benzene, dried in vacuo, andadded to 6.49 g. of butyl lithium in 50 ml. of dimethylsulfoxide. Thismixture is stirred until a red solution is obtained and 7.2 g. of6-hydroxy-6-methylheptan-2-one are then added. This mixture is stirredat about 25 C for 8 hours, poured into water, and this mixture isextracted with ether. The ether extracts are combined, washed with waterto neutrality, dried over sodium sulfate and reduced to dryness undervacuum. The residue, containing2-ethylenedioxy-6,IO-dimethyl-lO-hydroxyundec- 2-ene, is added to 100ml. of dry methanol containing 500 mg. of activated Spercentpalladium-on-charcoal catalyst. The mixture is hydrogenated at roomtemperature until 1.05 equivalents of hydrogen have been taken up; thenthe mixture is filtered. over a bed of Celite diatomaceous earth. Thefiltrate is added to 250 ml. of benzene, washed with several portions ofwater, dried over sodium sulfate and evaporated to dryness under vacuum.The residue, containing the desired 2-ethylenedioxy-6,10-dimethylundecan-lO-ol, is added to a 0.1 N solutionof hydrochloric acid in aqueous acetone and stirred for 15 hours. Themixture is then poured into ice water and extracted with ethyl acetate.After washing these extracts with water and drying them over sodiumsulfate, they are evaporated to yield10-hydroxy-6,10-dimethylundecan-Z-one which may be separated byfractional vacuum distillation or by preparative gas-liquidchromatography.

A mixture of 11.2 g. of diethyl carbethoxymethylphosphonate in 100 ml.of diglyme is treated with 2.4 g. of sodium hydride. This mixture isstirred until the evolution of gas ceases and 7.5 g. of10-hydroxy-6,10-dimethylundecan- 2-one are then slowly added withstirring, maintaining a temperature below 30 C. The mixture is stirredfor minutes and then diluted with water and extracted with ether. Theseethereal extracts are washed well with water, dried over sodium sulfateand evaporated to remove the solvent. The residue is subjected tofractional vacuum distillation to yield cis ethyl 3,7,11-trimethyl-11-hydroxydodec-2-enoate and trans ethyl 3,7,1 l-trimethyhl1-hydroxydodec2-enoate.

EXAMPLE 17 To a solution of 28.2 g. of trans, trans ethyl 3,7,11trimethyl-l1-hydroxydodeca-2,G-dienoate and 250 ml. of dry ethylacetate, 500 mg. of (4 percent) activated palladium-ontrimethyl-ll-hydroxydodec-Z-enoate which is purified by preparative scalegas-liquid chromatography.

Similarly, trans ethyl 3,7,11-trimethyl-l l-hydroxydodec-Z- enoate isprepared from trans, cis ethyl3,7,1l-trimethyl-1lhydroxydodeca-2,6-dienoate.

EXAMPLE 18 By the procedure described in Example 17 the compounds listedunder 11 are prepared from the respective compounds listed under 1.

l cis, trans 3,7,1l-trimethyl- 1 1-hydroxydodeca-2,6-dienoic acid cis,cis 3,7,ll-trimethyl-1lhydroxydodeca-2,6-dienoic acid trans, cis3,7,11-trimethyl- 1 l-hydroxydodeca-2,6-dienoic acid trans, trans methyl3,7,1 1- trimethyl-l l-hydroxydodeca- 2,6-dienoate trans, cis methyl3,7,1 l-trimethyl-1 l-hydroxydodeca-2,6'- dienoate trans, cis propyl3,7,1ltrimethyl-l l-hydroxydodeca 2,6-dienoate cis, cis isopropyl3,7,11- trimethyl-l l-hydroxydodeca- 2,6-dienoate cis, trans hexyl3,7,11- trimethyl-l l-hydroxydodeca- 2,6-dienoate trans, trans 3,7,1l-trimethyl-l l-acetoxydodeca-2,6 dienoic acid cis, trans3,7,114rimethyl- 1 l-trimethylacetoxy-2,6-dienoic acid trans, cis 3,7,1l-trimethyl- 1 l-benzoxydodeca-2,-dienoic acid trans, trans 3,7,1l-trimethyll 1-ethoxydodeca-2,6-dienoic acid cis, cis 3,7,1l-trimethyl-l 1- butoxydodeca-2,6-dienoic acid cis, trans 3,7,1l-trimethyll l-phenylethoxydodeca-2,fi-dienoic acid trans, cis 3,7,1l-trimethyl-l lcthoxydodeca-2,6-dienoic acid trans, trans methyl 3,7,1l-trimethyl-l1-methoxydodeca-2,6- dienoate cis, cis ethyl 3,7,1l-trimethyl- 1 l-ethoxydodeca-2,o-dienoate cis, trans ethyl 3,7,1l-trimethyl-l l-ethoxydodeca-2,6- dienoate trans, cis ethyl 3,7,1ltrimethyl-l 1-ethoxydodeca-2,6- dienoate trans, trans ethyl 3,7,1l-trimethyl-l l-ethoxydodeca-Z ,6- dienoate trans, trans butyl3,7,11-tri methyl-1 l-(tetrahydropyran-Z- yloxy )dodeca-2,6-dienoatecis, trans hexyl 3,7,1 l-trimethyl-1 l-(tetrahydrofuran-Z-yloxy)dodeca-2,6-dienoate trans, trans hexyl 3,7,1 l-trimethyl-ll-propoxydodeca-2,6- dienoate cis, cis octyl3,7,l1-trimethyl-1l-phenylethoxydodeca- 2,6-dienoate trans, trans ethyl3,7,1 l-trimethyl-l l-acetoxydodeca-2,6- dienoate cis, trans ethyl3,7,11-trimethyl-l 1-caproxydodeca-2,6- dienoate ll cis 3,7,1ltrimethyl-l lhydroxydodec-Z-enoic acid cis 3,7,11-trimethyL11-hydroxydodec-Z-enoic acid trans 3,7,11-trimethyl-11-hydroxydodec-2-enoic acid trans methyl 3,7,1 l-trimethyl-ll-hydroxydodec-L enoate trans methyl 3,7,11-trimethyl-1l-hydroxydodec-Z-enoate trans propyl 3,7,1 l-trimethyl-l l-hydroxydodec-Z- enoate cisisopropyl 3,7,1 l-trimethyl-1 l-hydroxydodec-Z- enoate cis hexyl3,7,11-trimethyl- 1 l-hydroxydodec-Z-enoate trans 3,7,1l-trimethyl-llacetoxydodec-2-enoic acid cis 3,7,l1-trimethyl-11-trimethylacetoxy-Z-enoic acid trans 3,7,1 l-trimethyl-llbenzoxydodec-Z-enoic acid trans 3,7,1l-trimethyl-1lethoxydodec2-enoicacid cis 3,7,1 l-trimethyl-l 1- butoxydodec-2-enoic acid cis3,7,ll-trimethyl-l1- phenylethoxydodecQ-enoic acid trans3,7,1l-trimethyi-1lethoxydodec-2-enoic acid trans methyl3,7,11-trimethyl-1l-methoxydodec-2- enoate cis ethyl 3,7,1 l-trimethyl-1 l-ethoxydodec-2-enoate cis ethyl 3,7,1 l-trimethyl- 11-ethoxydodec-2-enoate trans ethyl 3,7,1 l-trimethylll-ethoxydodec-Z-enoate trans ethyl 3,7,1 l-trimethyl- 11-ethoxydodec-2-enoate trans butyl 3,7,1 l-trimethyll 1-(tetrahydropyran-Z-yloxy)- dodec-2enoate cis hexyl 3,7,11-trimethyl- 11-(tetrahydrofuran-Z-yloxy)- dodec-Z-enoate trans hexyl3,7,1l-trimethyll l-propoxydodec-Z-enoate cis octyl 3,7,l1trimethyl- 11-phenylethoxydodec-Z-enoate trans ethyl 3,7,1 l-trimethyl- 1l-acetozydodec-Z-enoate cis ethyl 3,7,1l-trimethyl- 1l-caproxydodec-Z-enoate EXAMPLE 19 To a solution of 20.9 g. of theethylene ketal of l-bromohexan-4-one (obtained by treating1-bromo-4-hexanone with ethylene glycol in benzene in the presence ofp-toluenesulfonic acid) in 100 ml. of benzene is added 20 g. oftriphenylphosphine. This mixture is heated at reflux temperature for 2hours and then filtered. The solid material thus collected is washedwith benzene, dried in vacuo and added to 6.49 g. of butyl lithium in 50ml. of dimethylsulfoxide. This mixture is stirred until an orangesolution is obtained and 3.8 g. of ethyl methyl ketone is then added.This mixture is stirred at about 25 C for about 8 hours, poured intowater and this mixture is extracted with ether. The ethereal extractsare concentrated and the residue thus obtained is added to a 0.1 Nsolution of hydrochloric acid in aqueous acetone and stirred for abouthours. The mixture is then poured into ice water and extracted withethyl acetate. After washing these extracts with water and drying themover sodium sulfate, they are evaporated to yield a mixture of the cisand trans isomer of 7-methylnon-6-en-3- one which is separated bypreparative gas-liquid chromatography into the individual isomers.

To a solution of 20.9 g. of the ethylene ketal of lbromopentan-4-one in100 ml. of benzene is added g. of triphenylphosphine. This mixture isheated at reflux temperature for 2 hours and then filtered. The solidmaterial thus collected is washed with benzene, dried in vacuo and addedto 6.49 g. of butyl lithium in 50 ml. of dimethylsulfoxide. This mixtureis stirred until an orange solution is obtained and 5.5 g. of cis7-methylnon-6-en-3-one (the ketone obtained in Paragraph 1) is thenadded. This mixture is stirred at about C for about 8 hours, poured intowater and this mixture is extracted with ether. The ethereal extractsare concentrated and the residue thus obtained is added to a 0.1 Nsolution of hydrochloric acid in aqueous acetone and stirred for about15 hours. The mixture is then poured into ice water and extracted withethyl acetate. After washing these extracts with water and drying themover sodium sulfate, they are evaporated to furnish a mixture of thetrans, cis and cis, cis isomers of 6-ethyl-10-methyldodeca-5,9-dien-2-one which is separated by preparativegas-liquid chromatography to the individual isomers.

By repeating the above procedure with the exception of using trans7-methylnon-6-en-3-one in place of cis 7-methylnon-6-en-3-one, there isobtained a mixture of the cis, trans and trans, trans isomers of6-ethyl-10-methyldodeca-S ,9-dien- 2-onewhich is separated as describedabove.

Similarly, in the above procedure, instead of using either the trans orcis isomer of 7-methylnon-6-en-3-one as the starting material, there canbe used a mixture of the isomers obtained in Paragraph 1 hereof in whichcase a mixture of the four isomers is obtained which can then beseparated by preparative gas-liquid chromatography into the fourisomers.

A mixture of 11.2 g. of diethyl carbethoxymethylphosphonate in 100 ml.of diglyme is treated with 2.4 g. of sodium hydride. This mixture isstirred until the evolution of gas ceases and 7.5 g. of trans, cis6-ethyl-10-methyldodeca- 5,9-dien-2-one is then slowly added withstirring, maintaining a temperature below C. The mixture is stirred forabout 15 minutes and then diluted with water and extracted with ether.These ethereal extracts are washed well with water, dried over sodiumsulfate, and evaporated to remove the solvent to furnish a mixture ofthe trans,trans,cis and cis,trans,cis isomers of ethyl 3,11-dimethyl-7-ethyltrideca-2,6,IO-trienoate which is separated bypreparative gas-liquid chromatography.

The above procedure is repeated three times with the exception of usingcis, cis 6-ethyl-10-methyldodeca-S,9-dien-2- one as the startingmaterial the first time; trans, trans 6-ethyl-10-methylodeca-S,9-dien-2-one the second time; and cis, trans6-ethyl-lO-methyldodeca-S,9-dien-2-one the third time to obtain thecis,cis,trans and cis,cis,cis; the trans,trans,trans andtrans,trans,cis; and the cis,trans,trans and cis,trans,cis of ethyl3,11-dimethyl-7-ethyltrideca-2,6,lO-trienoate, respectively. The isomersare separated by preparative gas-liquid chromatography.

EXAMPLE 20 2 grams of methyl 3,7,1 l-trimethyltrideca-2,6,10-trienoatein 50 ml. of anhydrous ether is added over a 30-minute period to astirred suspension of 2 g. of lithium aluminum hydride in 50 ml. ofanhydrous ether at -20 C under nitrogen. This mixture is stirred at 20 Cfor 15 hours and then cautiously treated with about 10 ml. of ethylacetate and then about 4 ml. of water. The mixture is then filtered andthe solid thus collected is washed well with ether. The ether solutionis dried over sodium sulfate and evaporated to yield 3,7,1l-trimethyltrideca-2,6,10-trien-1-o1.

The procedure of this example is repeated with the exception that methyl3,7,11-trimethyltrideca-2,6,IO-trienoate is replaced with the esterspreferably the methyl esters, described hereinabove, for example, thoseExamples 1 through 4 to furnish the corresponding free alcohol at C-l,for example, 3,7,11-trimethyldodeca-2,6,IO-trien-1-ol 3,11-dimethyl-7-ethyltrideca-2,6,IO-trien-l 3,7-diethyl-llmethyltrideca-2,6,10-trien-1-o1, 3,1 1-dimethyl-7-ethyldodeca-2,6,10-trien-l-o1, 7,1 1-dimethyl-3-ethyltrideca-2,6, 1 O-trien- 1-01,7,11-dimethyl-3-ethylododeca-2,6,l0trien-1-o1, and the like.

Similarly, the C-lalcohol corresponding to the 2,6-diene, 1,10-diene and2ene esters of Examples 8 through 17 are obtained by treatment withlithium aluminum hydride using the procedure of this example, forexample,

3,7,1 1-trimethyldodeca-2,6-dien-l-ol,

3,7-dimethyl-1 1-ethyltrideca-2,10-dien- 1 01,

3,1 l-dimethyl-7-ethyltrideca-2,lO-dien-1-o1,

3 ,7-diethyl-l l-methyltrideca-2,10-dien-1-o1,

3,1 1-dimethyl-7 ethyldodeca-2,10-dien-l-o1,

3,7-diethyl-1 l-methyldodec-Z-en-l -o 1,

3,7,1 l-triethyltrideca-2,10-dien-l-ol,

3,7,1 l-trimethyltrideca-2,lO-dien-l-01, and

3,7,1 1-trimethyldodeca-2,6-dien-l ,1 l-diol from ethyl 3,7,11-trimethyldodeca-2,6-dienoate,

ethyl 3,7-dimethyl-1 l-ethyltrideca-Z,10-dienoate,

ethyl 3,1 1-dimethyl-7-ethyltrideca-2,IO-dienoate,

ethyl 3 ,7-diethyl-1 1 -methyltrideca-2, 1 O-dienoate,

ethyl 3,1 1-dimethyl-7-ethyldodeca-Z,10-dienoate,

ethyl 3,7-diethy1-1 l-methyldodec-l-enoate,

ethyl 3,7,1 l-triethyltrideca-2,IO-dienoate,

ethyl 3,7,1 1-trimethyltrideca-2,10-dienoate, and

ethyl 3,7,1 l-trimethyl-l l-hydroxydodeca-2,6-dienoate, respectively.

are obtained EXAMPLE 21 A mixture of l g. of3,7,11-trimethyltrideca-2,6,lO-trien-l- 01, 4 ml. of pyridine and 2 ml.of acetic anhydride is allowed to stand at room temperature for 15hours. The mixture is then poured into water and stirred. The mixture isextracted with methylene chloride and the organic extracts are dried andevaporated to yield 1-acetoxy-3,7,1l-trimethyltrideca- 2,6, l O-triene.

By repeating the above process using as the starting material, other C-lalcohols prepared hereinabove, the corresponding acetate is obtained,e.g. 1-acetoxy-3,7,1 l-trimethyldodeca-2 ,6,10-triene, l-acetoxy-3 ,ll-dimethyl-7-ethyltrideca-2,6,10-triene, 1-acetoxy-3 ,7-diethyl-1l-methyltrideca-2,6,10-triene, 1acetoxy-3,1 l-dimethyl-7-ethyldodeca-2,6, l O-triene, 1-acetoxy-7,1 1-dimethyl-3-ethyltrideca-2,6, l 0-triene, l-acetoxy-7,l l-dimethyl13-ethyldodeca12,6,l0- triene, and thelike.

Similarly, by using other carboxylic acid anhydrides in the process ofthis example in place of acetic anhydride, for example, propionicanhydride, n-butyric anhydride, n-caproic anhydride, and the like, thecorresponding l-acylates are obtained, e.g. l-propionate, l-butyrate,and the like.

EXAMPLE 22 28 grams of 3,7,11-trimethyltrideca-2,6,IO-trien-l-ol isadded to a suspension of 3.0 g. of sodium hydride in 110 ml. of benzene,this mixture is stirred until the evolution of hydrogen ceases and then47 g. of ethyl iodide is added with stirring. The mixture is refluxedfor 2 hours and then washed with water. Evaporation of solvent in vacuofurnishes the ethyl ether of 3,7,11-trimethyltrideca-2,6,10-trien-1-o1which is purified by chromatography.

Through the use of other alkyl halides, such as methyl iodide, propylbromide, and the like, in place of ethyl iodide, the correspondingmethyl ether, propyl ether, and the like, are obtained.

By repeating the process of this example with the exception ofsubstituting other Cl alcohols in place of 3,7,1l-trimethyltrideca-2,6,10-trien-l -o l e. g. 3 ,7,1l-trimethyldodeca-2,6,10- trien- 1 -ol, 3 ,1 l-dimethyl-7-ethyltrideca-2,6,1 O-tn'en- 1 -ol 3 ,7-diethyl-l l-methyltrideca-2,6,10-trienl -o 1and the like, the corresponding ether, methyl ether, propyl ether, andthe like, are obtained.

EXAMPLE 23 a solution of 1.2 g. of methyl 3,7,1 l-trimethyltrideca-2,6,10-trienoate in 5 ml. of dimethylsulfoxide is added to a solution of1 equivalent of dimethylsulfoxonium methylide in dimethylsulfoxide[prepared by the procedure of Corey et al., J. Am. Chem. Soc. 87, 1353(1965)]. The mixture is stirred under nitrogen and at room temperaturefor about 20 hours and then at 50 C for about 7 hours. 50 ml. of wateris then added and the resulting mixture extracted 4 times with 50 ml. ofethyl acetate. The combined extracts are washed with water and saturatedaqueous sodium chloride solution, dried and evaporated to furnish methyl2,3-methylene-3,7,1l-trimethyltrideca-6,10-dienoate which is purified bysilica chromatography.

By using as the starting material in the process of this exam ple, other2,6,1 O-trienoates described herein (see Examples 1- 5, for example),there are obtained the corresponding 2,3- methylene-6,10-dienoates,e.g., methyl 2,3-methylene-3,7,1 1- tri-methyldodeca-6,IO-dienoate,methyl 2,3-methylene-3,l1- dimethyl-7-ethyltrideca-6,IO-dienoate, ethyl2,3-methylene- 3,7,11-tri-methyldodeca-6,10-dienoate, ethyl2,3-methylene- 3,1 1 dimethy1-7-ethy1trideca-6,10-dienoate, ethyl 2,3-methylene-3,11-dimethy1-7-ethylodedca-6,10-dienoate, ethyl 2,3 -methylene-3 ,7 ,1 1-trimethyl-trideca-6,IO-dienoate, ethyl2,3-methylene-3-ethyl-7,1 1-dimethyl-trideca-6,10-dienoate, ethyl 2,3-methylene-3-ethyl-7, 1 l-dimethyl-dodeca-6, l 0- dienoate, ethyl2,3-methylene-3,7-diethyl-1l-methyl-trideca- 6,10-dienoate, and thelike.

By using as the starting material in the process of this example, theethyl esters of Examples 8-17 and 19 and the esters of Example 18, thecorresponding 2,3-methylene esters are obtained. For example,

ethyl 2,3-methylene-3,7,1 1-trimethy1dodec-6-enoate,

ethyl 2,3-methylene-3 ,7-dimethyl- 1 1 -ethyltridec-10- enoate,

ethyl 2,3-methylene-3,1 1-dimethyl-7-ethyltridec-l0- enoate,

ethyl 2,3-methylene-3 ,7-diethy1-l 1 -methyltridec-1 0- enoate,

ethyl 2,3-methylene-3 ,1 1-dimethy1-7-ethyldodec-10- enoate,

ethyl 2,3-methylene-3 ,7-diethyl-1 1 -methyldodec-1 0- enoate,

ethyl 2,3 -methylene-3 ,7-diethyl-l l-methyldodecanoate,

ethyl 2,3-methylene-3,7,1 1-triethyltridec-10-enoate,

ethyl 2,3-methylene-3,7,1 1-trimethyltridec-10-enoate,

ethyl 2,3-methylene-l 1-hydroxy-3,7,1 1-trimethy1dodec-6- enoate,

ethyl 2,3-methylene-3,7,l l-trimethyldodecanoate,

ethyl 2 ,3-methylene-7-ethyl-3 ,1 l-dimethyltridecanoate, and

' methyl ethyl 2,3-methylene-3,7,11-trimethyldodec-lO-enoate areobtained from the corresponding ethyl 2,6-dienoate, ethyl 2,10-dienoateand ethyl 2-enoate.

By subjecting the thus-prepared 2,3-methylene-2,6- dienoates to theprocedures of Examples 6, 20, 21 and 22, the corresponding free acids,free alcohols, esters and ethers, respectively, are obtained, e.g.,2,3-methyIene-3,7,11- trimethyltrideca-6,10-dienoic acid,2,3-methylene-3,7,l1- trimethyltrideca-6,l0-dien1-o1, 1-acet0xy-2,3-methylene- 3 ,7,1 l-trimethyltrideca-6,IO-diene,1-ethoxy-2,3-methy1ene- 3,7,1 l-trimethyltrideca-6,10-diene, and thelike.

EXAMPLE 24 A mixture of 7 g. of methylene iodide and 3 g. of zinccoppercouple in 15 ml. of anhydrous ether is heated at reflux under nitrogenfor 3 hours. The mixture is then cooled and 2 g. of methyl3,7,1l-trimethyltrideca-2,6,IO-trienoate added. This mixture is allowedto stand at room temperature for 2 hours and is then poured into 200 m1.of 2 percent aqueous sodium carbonate and extracted twice with ml.portions of ether. The extracts are dried over sodium sulfate andevaporated under reduced pressure. The oily residue is held at 0.01 mm.to remove any unreacted methylene iodide and then purified by gas-liquidchromatography to obtain methyl 6,7- methylene-3 ,7,11-trimethyltrideca-2,10-dienoate, methyl 10,1 l-methylene-3,7,11-trimethyltrideca-2,6-dienoate,

6,7;10,1 1-(bis)methylene-3,7,1l-trimethyltridec-Z- enoate.

By using the 2,3methylene compounds of Example 23 as the startingmaterial in the above process, there is obtained methyl 2,3;6,7;10,11-(tris)methylene-3,7,1 l-trimethyltridecanoate, methyl 2,3;6,7-(bis)methy1ene-3,7,I 1- trimethyltridec-l l-enoate, and methyl2,3;10,l 1- (bis)methylene-3,7,1 1-trimethyltridec-6-enoate, ethyl2,3;6,7-(bis)methylene-3,7,1 l-trimethyldodecanoate, ethyl 2,3;10,11-(bis)methylene-3,7-dimethyl-1 l-ethyltridecanoate, ethyl 2,3;10,11-(bis)methylene-3,l1-dimethyl-7-ethyltridecanoate, ethyl2,3;10,11-(bis)methylene-3,l l-dimethyl-7 -ethyldodecanoate, ethyl2,3;10,1l-(bis)methylene-3,7- diethyl-1 l-methyldodecanoate, ethyl 2,3 1O, 1 1- (bis)methylene-3,7,1 l-trimethyldodecanoate, and the like.

By repeating the procedure of this example using other alkyl estersdescribed herein (e.g. Examples 1-5, 8-15 and 19), the correspondingmethylene and (bis)methylene compounds are obtained. For example,

ethyl 10,1 1-methylene-3 ,7,1 1-trimethyldodeca-2,6- dienoate,

ethyl 6,7 l 0,1 1-bismethylene-3 ,7 ,l l-trimethyldodec-Z- enoate, and

ethyl 6,7 -methylene-3 ,7 ,1 1 -trimethyldodeca-2 l O-dienoate;

ethyl 10,1 1-methylene-3,1 1-dimethyl-7-ethyltrideca-2,6- dienoate,

ethyl 6,7-methylene-3 ,1 1-dimethyl-7-ethyltrideca-2, l 0- dienoate, and

ethyl 6,7;10,1 l-bismethylene-3,l 1-dimethyl-7-ethyltridec- 2-enoate;

ethyl 10,1 l-methylene-3,l l-dimethyl-7-ethyldodeca-2,6- dienoate,

ethyl 6,7-methylene-3,1 1-dimethyl-7-ethyldodeca-2,10-

dienoate, and

ethyl 6,7;10,1 l-bismethylene-3 ,1 l-dimethyl-7-ethyldodec- Z-enoate;

ethyl 10,1 l-methylene3 ,7-dimethyl-1 1-ethyltrideca-2,6- dienoate,

ethyl 6,7-methylene-3 ,7-dimethyl-1 1-ethyltrideca-2,10-

10,1 l-methylene-3,7,1 1-trimethyltrideca-2,6

ethyl 6,7;10,1 1-bismethylene-3,7,l l-trimethyltridec-2- enoate areobtained from ethyl 3,7,1 l-trimethyldodeca-2,6,IO-trienoate,

ethyl 3,1 1-dimethyl-7-ethyltrideca-2,6,IO-trienoate,

ethyl 3,1 1-dimethyl-7-ethyldodeca-2,6,lO-trienoate,

ethyl 3,7-dimethyl-1l-ethyltrideca-2,6,IO-trienoate, and

ethyl 3,7,1l-trimethyltrideca-2,6,IO-trienoate, respectively.

The corresponding acids can be obtained using the procedure of Example 6and the corresponding saturated derivatives can be obtained byhydrogenation using the procedure of, for example, Example 7.

EXAMPLE 25 To a mixture of 2 g. of 3,1l-dimethyl-7-ethyltrideca-2,6,10-trien-l-ol in 150 ml. of methylene chloride at C, there is slowly added1.0 molar equivalent of m-chloroperbenzoic acid in 100 ml. of methylenechloride. The resulting mixture is then allowed to stand for 15 minutesat 0 C and then washed with 2 percent aqueous sodium sulfite solution,with percent aqueous sodium bicarbonate solution and with water, driedover sodium sulfate and evaporated to an oil which contains a mixture ofthe 10,1l-epoxide, 6,7-epoxide and a small amount of the6,7;10,l1-(bis)epoxide of 3,11-dimethyl-7-ethyltrideca-2,6,10-trien-l-ol. This mixture is then purified and separated into theindividual epoxides by chromatography on silica, i.e., 10,1 1-oxido-3,l1-dimethyl-7-ethyltrideca-2,6-dien-l-ol, 6,7- oxido-3,l1-dirnethyl-7ethyltrideca-2,10-dien-l-ol, and 6,7 l 0,1 l-(bis)oxido-3,l l-dimethyl-7-ethyltridec-2-en-1-ol.

By repeating the process of this example with the exception of using asthe starting material other 2,6,10-trienes described herein, e.g.,1-acetoxy-3,1 l-dimethyL7-ethyltrideca- 2,6,l0triene, methyl ether of3,1l -dimethyl-7-ethyltrideca- 2,6,lO-triene-l-ol, methyl3,1l-dimethyl-7-ethyltrideca- 2,6,l0l-trienoate, methyl3,7,1l-trimethyltrideca-2,6,l0- trienoate, methyl3,7,11-trimethyldodeca-2,6,IO-trienoate, methyl 3,7-diethyl-l1-methyltrideca-2,6,10-trienoate, 3,7,1 1- trimeth yltrideca-2,6, lO-trienoic acid, 3 ,7,1 1 -trimethyldodeca-2,6,10-trienoic acid,3,11-dimethyl-7-ethyltrideca- 2,6,l0-trienoic acid3,7-diethyl-1l-methyltrideca-2,6,l0- trienoic acid,3,7-diethyl-1l-methyltrideca-2,6,lO-trien-l-ol,3,7,1l-trimethyltrideca-2,6,IO-trien-l-ol, and the like, in place of3,1l-dimethyl-7-ethyltrideca-2,6,IO-trien-l-ol, the corresponding10,1l-epoxides, 6,7-epoxides and a small amount of the6,7;10,1l-(bis)epoxides are obtained, e.g.,

l-acetoxy-l0,1 l-oxido-3,l1-dimethyl-7-ethyltrideca-2,6- diene,

methyl ether of 3,1l-dimethyl-7ethyl-l0,ll-oxidotrideca- 2,6-dien-l-olmethyl dienoate,

methyl 10,1 1-oxido-3,7,1 l-trimethyltrideca-2,6-dienoate,

methyl 10,1 l-oxido-3,7,l 1-trimethyldodeca-2,6-dienoate,

methyl 10,1 l-oxido-3,7-diethyl-l l-methyltrideca-2,6- dienoate,

10,1 l-oxido-3,7,1 l-trimethyltrideca-2,6-dienoic acid,

10,1 1-oxido-3,7,1 l-trimethyldodeca-2,6-dienoic acid,

10,1 1-oxido-3,l l-dimethyl-7-ethyltrideca-2,6-dienoic acid,

10,1 l-oxido-3,7-diethyl-l 1-methyltrideca-2,6-dienoic acid,

10,1 l-oxido-3,7-diethyl-l l-methyltrideca-2,6-dien-l-ol,10,1l-oxido-3,7,ll-trimethyltrideca-2,6-dien-l-ol, and the like, and thecorresponding 6,7-epoxide and 6,7;10,11(bis)epoxide.

By use of the procedure of this example, there is obtained,

ethyl 10,1 l-oxido-3,7,l 1-trimethyldodeca-2,6-dien0ate,

ethyl 6,7-oxido-3,7,l 1-trimethyldodeca-2,IO-dienoate, and

ethyl 6,7; 10,1 1-bisoxido-3 ,7,l l-trimethyldodec-2-enoate;

10,1 l-oxido-3,1 1-dimethyl-7-ethyltrideca-2,6-

ethyl 10,1 l-oxido-3,1 l-dimethyl-7-ethyltrideca-2,6- dienoate,

ethyl 6,7-oxido-3,l l-dimethyl-7-ethyltrideca-2,l0-

dienoate, and

ethyl 6,7;l0,l l-bisoxido-3,l 1-dimethyl-7-ethyltridec-2- enoate;

ethyl 10,1 l-oxido-3,l l-dimethyl-7-ethyldodeca-2,6- dienoate,

ethyl 6,7-oxido-3,l 1-dimethyl-7-ethyldodeca-2,l0- dienoate, and

ethyl 6,7;l0,l 1-bisoxido-3,l l-dimethyl-7-ethyldodec-2- enoate;

ethyl 10,1 l-oxido-3,7-dimethyl-l l-ethyltrideca-2,6- dienoate,

ethyl 6,7-oxid0-3,7-dimethyl-l l-ethyltrideca-2,10- dienoate, and

ethyl 6,7;10,l l-bisoxido-3,7-dimethyl-l l-ethyltridec-2- enoate;and

ethyl 10,1 1-oxido-3,7,l 1-trimethyltrideca-2,6-dienoate,

ethyl 6,7-oxido-3,7,l l-trimethyltrideca-2,IO-dienoate, and

ethyl 6,7;10,1 1-bisoxido-3,7,1 l-trimethyltridec-2-enoate from ethyl 3,7,1 l-trimethyldodeca-2,6, l O-trienoate,

ethyl 3,1 1-dimethyl-7-ethyltrideca-2,6,lO-trienoate,

ethyl 3,1 l-dimethyl-7-ethyldodeca-2,6,l0-trienoate,

ethyl 3,7-dimethyl-1 l-ethyltrideca-2,6,IO-trienoate, and

ethyl 3,7,1 1-trimethyltrideca2,6,IO-trienoate, respectively.

By use of the procedure of this example, the 2,3- methylenes,6,7-methylenes, 10,11-methylenes, 2,3;6,7-bismethylenes and2,3,10,11-bismethylenes of Examples 23 and 24 having unsaturation atC-6,7, C-10,11 or C-6,7;l0,l1 are converted into the corresponding monoand/or bis-epoxide. For example,

ethyl 2,3-methylene-10,l l-oxido-3,7,1 l-trimethyldodeca- 6-enoate,

ethyl 2,3-methylene-6,7-oxido-3,7,l l-trimethyldodec-IO- enoate, and

ethyl 2,3-methylene-6,7;l0,l l-bisoxido-3,7,l l-trimethyldodecanoate;

ethyl 2,3-methylene-10,1l-oxido-3,7,l 1-trimethyltridec-6- enoate,

ethyl 2,3-methylene-6,7-oxido- 3,7,11-trimethyltridec-10- enoate, and

ethyl 2,3-methylene-6,7;10,1 l-bisoxido-3,7,l l-trimethyltridecanoate;

ethyl 2,3-methylene-l0,1 l-oxido-3,l l-dimethyl-7-ethyltn'dec-6-enoate,

ethyl 2,3-methylene-6,7-oxido-3,1 l-dimethyl-7-ethyltridec- IO-enoate,and

ethyl 2,3-methylene-6,7;l0,l lbisoxido 3,11-dimethyl-7-ethyltridecanoate;

ethyl 10,1 lmethylene-6,7-oxido-3 ,1 1-dimethyl-7-ethyltridec-Z-enoate;

ethyl 6,7-methylenel 0,1 l-oxido-3 ,1 1-dimethyl-7 -ethyl- 10,11-methylene-3,l l-dimethyl-7-ethyltrideca-2,6-

enoate and ethyl 3,1 l-dimethyl-7-ethyl-l0,l l-oxidotridecanoate.

EXAMPLE 26 Anhydrous hydrogen chloride is introduced into 100 ml. ofether at C until a saturated solution is obtained. 1 gram of methyl3,7,1l-trimethyltrideca-2,6,l0-trienoate is added and the resultingmixture is then allowed to stand at 0 C for 4 days. The mixture is thenevaporated under reduced pressure to an oil which is purified by silicachromatography to furnish methyl 7,1l-dichloro-3,7,l1-trimethyltridec-2-enoate.

Through the use of other 2,6,l0-triunsaturated compounds describedherein as the starting material in the above process, the corresponding7,1 l-dichloro derivatives are obtained, e.g., methyl 7,1l-dichloro-3,7,l l-trimethyldodec-2-enoate, methyl 7,1 l-dichloro-3,ll7-ethyltridec-2-enoate, 7,1 ldichloro-3,7,1l-trimethyltridec-2-enoicacid, 7,1 l-dichloro- 3,7,1l-trimethyldodec-2-enoic acid, 7 ,1l-dichloro-3,1 ldirnethyl-7-ethyltridec-2-enoic acid, and the like.

By use of the above procedure, there is prepared ethyl 7,1ldichloro-3,7,1 1-trimethyldodec-2-enoate, ethyl 7,1 1-dichloro-3,11-dimethyl-7-ethyltridec-2-enoate, ethyl 3,1 l-

dichloro-3 ,1 l-dimethyl-7-ethyldodec-2-enoate, ethyl 7 ,l 1- dichloro-3,7-dimethyl-l l-ethyltridec-Z-enoate, and ethyl 7 ,1 1-dichloro-3 ,7 ,ll-trimethyltridec-2-enoate from ethyl 3,7,11-trimethyldodeca-2,6,lO-trienoate, ethyl 3,1 l-dimethyl-7-ethyltrideca-2,6,IO-trienoate, ethyl3,1l-dimethyl-7-ethyldodeca-2,6,l0-trienoate, ethyl3,7-dimethyl-ll-ethyltrideca- 2,6,10-trienoate, and ethyl3,7,11-trimethyltrideca-2,6,l0- trienoate, respectively.

Similarly, by using the 2,3-methylene-6,l0-dienoates of Example 23 asthe starting material in the procedure of this example, thecorresponding 7,1l-dichloro compounds are obtained. For example, ethyl7,1l-dichloro-2,3-methylene-3,l ldimethyl-7-ethyltridecanoate and ethyl7,l1-dichloro-2,3- methylene-3,7,1l-trimethyldodecanoate from ethyl 2,3-methylene-3,l l-dimethyl-7-ethyltrideca-6,lO-dienoate and ethyl2,3-methylene-3,7,11-trimethyldodeca-6,IO-dienoate, respectively.

7,11-Dichloro compounds having saturation at C-2,3 are prepared from thecorresponding 6,10-diene compound or by hydrogenation of7,1l-dichloro-2-ene compounds using the procedure of Example 7.

EXAMPLE 27 Chlorine gas is bubbled into 200 ml. of carbon tetrachlorideat 0 C until a 0.5 molar solution is obtained. 25 grams of methyl3,7,11-trimethyltrideca-2,6,lO-trienoate is added and the mixture isthen stirred and allowed to stand at 0 C for 24 hours. The mixture isthen evaporated to furnish an oil containing methyl 10,11-dichloro-3,7,11-trimethyltrideca-2,6- dienoate, methyl 6,7-dichloro-3,7,11-trimethyltrideca-2,l0- dienoate and methyl6,7,l0,1l-tetrachloro-3,7,ll-trimethyltridec-Z-enoate which are purifiedand separated by gas-liquid chromatography or alternatively purificationand separation can be made by 2 distillations through a spinning bandfractionation column.

The above process is repeated with the exception of using as thestarting material other 2,6,10-triunsaturated compounds described hereinin place of methyl 3,7,1 l-trimethyltrideca- 2,6,10-trienoate, e.g.methyl 3,7,1l-trimethyldodeca-2,6,10- trienoate, methyl 3,1l-dimethy1-7-ethyltrideca-2,6,10- trienoate, 3,7,1l-trimethyltrideca-2,6,10-trienoic acid,

. 3,7,1 1'trimethyldodeca-2,6,10-trienoic acid, 3,1 1-dimethy1-7-ethyltrideca-2,6,lO-trienoic acid, 3,7,l1-trimethyltrideca- 2,6, lO-trien- 1 -01, 3,7,1 l-trimethylodeca-2,6, l O-trien- 1 -ol, 3,1l-dimethyl-7-ethyltrideca-2,6,10-trien-l-ol, l-acetoxy- 3,7,11-trimethyltrideca-2,6,l0-trien, l-acetoxy-3,7,1 1- trimethyldodeca-2,6,l O-triene, l-acetoxy-3,l 1-dimethyl-7- ethyltrideca-2,6,lO-trien,1-acetoxy3,l l-dimethyl-7-ethyltrideca-2,6,lO-triene, 1-methoxy-3,7,ll-trimethyltrideca- 2,6, l O-triene, 1-methoxy-3,7,l1-trimethyldodeca-2,6,l0-

trien, l-methoxy-3,1 l-dimethyl-7ethyltrideca-2,6,IO-triene, and thelike, and there are obtained the corresponding 10,1 1- dichloroderivatives, 6,7-dichloro derivatives and 6,7,10,11- tetrachloroderivatives, e.g. methyl l0,ll-dichloro-3,7,11-trimethyldodeca-2,6-dienoate, methyl6,7-dichloro-3,7,lltrimethyldodeca-2,lO-dienoate, methyl 6,7,lO,lltetrachloro- 3,7,1l-trimethyldodec-2-enoate, and the like. The C- 1alcohol, l-acetoxy and l-methoxy compounds also furnish C- 2,3 dichloroderivatives which can be separated by chromatography.

By repeating the above procedure using ethyl 3,7,11-trimethyldodeca-2,6,IO-trienoate, ethyl 3,11-dimethyl-7-ethyltrideca-2,6,IO-trienoate, ethyl 3,1l-dimethyl-7-ethyldodeca-2,6,l0-trienoate, ethyl 3,7-dimethyl-ll-ethyltrideca- 2,6,l0-trienoate and ethyl3,7,11-trimethyltrideca-2,6,l0- trienoate, respectively, as the startingmaterial, the corresponding ethyl 10,1l-dichloro-2,6-dienoate, ethyl6,7- dichloro-2,l0-dienoate and ethyl 6,7,l0,ll-tetrachloro-2- enoatederivatives are obtained.

By repeating the procedure outlined in this example except forsubstituting bromine for chlorine, a mixture of the correspondingbrominated compounds is prepared and separated by chromatography.

Use of a mixed halogen reagent, such as chlorine-fluorine in thisprocedure provides the corresponding mixed dihalo compounds.

In like manner, the corresponding 6,7-dibromo; l0,lldibromo; and6,7,10,1l-tetrabromo derivatives of starting compounds ethyl 3,7,1l-trimethyltrideca-2,6,lO-trienoate and ethyl3,1l-dimethyl-7-ethyltrideca-2,6,lO-trienoate are prepared.

EXAMPLE 28 Ethyl 3,7,1l-trimethyl-l0,ll-oxidododeca-2,6-dienoate isprepared as described in Example 25 and is thereafter treated by theprocedure of Example 27 to afford ethyl 3,7,1 1- trimethyl-6,7-dichloro-10,1 l-oxidododec-Z-enoate. By repeating this procedure with thosecompounds not containing the a, B-unsaturated carbonyl system, thecorresponding 6,7- dichloro-l0,ll-oxido derivative is separated from.the final reaction mixture by chromatography from the presence of someof the corresponding 2,3,6,7-tetrachloro-l0,l l-oxido compound. 7

Similarly obtained are ethyl 3,7,1l-trimethyl-6,7-dichloro- 10,1l-oxidotridec-Z-enoate and ethyl 3,1 l-dimethyl-6,7 dichloro-7ethyl-l0,ll-oxidotridec-Z-enoate as well as the corresponding methyl estersthereof.

EXAMPLE 29 The process of Example 27 is repeated with the exception thatmethyl 10,1 l-oxido-3,7,l 1-trimethyltrideca-2,6-dienoate is employed asthe starting material in place of methyl 3,7,1 1-trimethyltrideca-2,6,lO-trienoate and there is obtained methyl6,7-dich|oro-l0,113,7,11-trimethyltridec-2-enoate which can be purifiedby chromatography or fractional distillation.

By substituting other 10,1l-oxido-2,6-diunsaturated compounds describedherein as the starting material in this example, e.g. methyl 10,1l-oxido-3,7,1 l-trimethyldodeca-2,6- dienoate, methyll0,ll-oxido-7-ethyl-3,ll-dimethytrideca- 2,6-dienoate, 10,1l-oxido-3,7,l l-trimethyltrideca-2,6-dien- 101, 10,1l-oxido-3,7,1l-trimethyldodeca-2,6-dien-1-ol, 10,1l-oxido-3,11-dimethyl-7-ethyltrideca-2,6-dien-1-ol,

10,1 1-oxido-l-acetoxy-3,7 ,1 l-trimethyltrideca-2,6-diene, 10,1l-oxido-l-acetoxy-3,7,l l-trimethyldodeca-2,6-diene, I 0,1l-oxido-1-acetoxy-3, l 1-dimethyl-7-ethyltrideca-2,6-

diene, 10,1 l-oxido-l-methoxy-3,7,1 l-trimethyltrideca-2,6- diene,10,1l-oxido-l-methoxy-3,7,ll-trimethyldodeca-2,6- diene, 10,11-oxido-l-methoxy-3,l l-dimethyl-7-ethyltrideca- 2,6-diene, 10,1l-oxido-3,7,l 1-trimethyltrideca-2,6-dienoic acid,10,11-oxido-3,7,11-trimethyldodeca-2,6-dienoic acid, 10,1 l-oxido-3,l1-dimethyl-7-ethyltrideca-2,6-dienoic acid,

3] and the like, the corresponding 6,7-dichloro-10,ll-oxido compoundsare obtained, e.g. methyl 6,7-dichloro-l0,1loxido-3,7,ll-trimethyldodec-2-enoate, methyl 6,7-dichloro- 10,1 1-oxido-7ethyl-3,ll-dimethyltridec-2-enoate, 6,7-dichloro-10,11-oxido-3,7,1l-trimethyltridec-Z-en-l-ol, 6,7-dichloro-10,l1-oxido-3 ,7 ,l l-trimethydodec-Z-en- 1 -ol, and

the like.

EXAMPLE 30 Anhydrous hydrogen chloride is bubbled into 100 ml. of carbontetrachloride at C until a saturated solution is obtained. 1 gram ofmethyl 3,7,11-trimethyltrideca-2,6,10- trienoate is added and theresulting mixture is then allowed to stand at 0 C for 4 days. Then themixture is evaporated under reduced pressure to an oil which is purifiedby column chromatography to furnish methyl l1-chloro-3,7,ll-trimethyltrideca-2,6-dienoate. B The process of this example isrepeated with the exception of substituting other 2,6,10- trienoatesprepared hereinabove, e.g. those of Examples 2-5, for the startingmaterial and there is obtained the corresponding 1l-chloro-2,6-dienoate,for example methyl ll-chloro- 3,7,11-trimethyldodeca-2,6-dienoate,methyl 1l-chloro-3,1ldimethyl-7'-ethyltrideca-2,6-dienoate, methyll1-chloro-3,7- diethyl-l l-methyltrideca-2,o-dienoate, and the like,ethyl 1 lchloro-3,7,1l-trimethyltrideca-2,6-dienoate, ethyl ll-chloro-3,7,1 1-trimethyldodeca-Z,6-dien0ate, and the like.

By repeating the process of this example with the exception ofsubstituting the corresponding 2,6,10-trienoic acids preparedhereinabove, (see, for example, Example 6) as the starting material inplace of the 2,6,l0-trienoate employed above, the corresponding 11-chloro-2,6-dienoic acids are obtained, e.g. 1l-chloro-3,7,ll-trimethyltrideca-2,6-dienoic acid,1l-chloro-3,7,11-trimethyldodeca-2,6-dienoic acid, 11-chloro-3,l1-dimethyl-7-ethyltrideca-2,6-dienoic acid, 11-chloro-3,7-diethyl-11-methyltrideca-2,6-dienoic acid, 1lchloro-3,ll-dimethyl-7-ethyldodeca-2,6-dienoic acid, 11-chloro-7,ll-dimethyl-3-ethyltrideca-2,6-dienoic acid, 11- chloro-7,11-dimethyl-3-ethyldodeca-2,6-dienoic acid, and the like.

EXAMPLE 31 lnto a solution of 5 g. of methyl 10,1 l-oxido-3,7,lltrimethyldecanoate (obtained by hydrogenation of the corresponding A10,1 l-epoxide on 5 percent Pd/C) in 100 ml. of CCl is slowly bubbledhydrogen fluoride at 0 C with stirring. When about 1 chemical equivalenthas been added, the mixture is allowed to stand for 6 hours, washed withwater and evaporated to an oil which is chromatographed on silica togive methyl 10-hydroxy-l l-fluoro-3,7,l l-trimethyltridecanoate andmethyl 10-fluoro-1 l-hydroxy-3,7,1ltrimethyltridecanoate.

By substituting in the above process as the starting material methyl10,1 l-oxido-3,7, l l -trimethyItrideca-2,-dienoate, there is obtainedthe corresponding IO-hydroxy-l l-fluoro and IO-fluoro-l l-hydroxyderivatives containing a fluoro atom at position C-7.

The process of this example is repeated with the exceptions that 0.1 Nhydrogen fluoride in anhydrous methanol is used as the reagent andreaction medium and the reaction is run for 3 days at room temperatureand there is. obtained the corresponding substitution productIO-fluoro-l l-methoxy derivative. Use of other lower monohydric alcoholsas the reaction medium provides the corresponding alkoxy derivatives.

To 5 grams of methyl lO-hydroxy-l l-fluoro-3,7,l ltrimethyltridecanoatein 100 ml. of anhydrous ether, is added 1 chemical equivalent ofdiazomethane. 1 drop of boron/trifluoride is then added and the reactionmixture is allowed to stand at 0 C for 1 hour and then at roomtemperature for 2 additional hours. Thereafter, the mixture is washedwith water, evaporated and chromatographed to give methyl lO-methoxy-ll-fluoro-3,7,1 l-trimethyltridecanoate.

By use of other diazoalkanes, such as diazoethane, the correspondingalkoxy derivatives are prepared, such as the 10- ethoxy compounds.

EXAMPLE 32 A. To a solution of 2 g. of methyl 7,1l-dichloro-3,7,l1-trimethyltridec-Z-enoate in anhydrous ether 50 ml.) at 0 C is added withstirring lithium aluminum hydride (0.36 g.). After 1 hour, acetic acid(2.4 ml.) is added. The mixture is washed with ice water and the etherphase dried and evaporated to give7,1l-dichloro-3,7,1l-trimethyltridec-Z-en-l-ol.

By using other 7,1l-dichloro esters (see Example 26, for example), thecorresponding C-l alcohols are obtained.

By the procedure of Example 21, the above C-l alcohols are convertedinto the corresponding acylates, e.g. acetates.

By the procedure set forth in paragraph 4 of Example 31, the above C-lalcohols are converted to the corresponding ether.

B. Likewise, the alkyl ll-monochloro 2,6-dienoates, e.g. methyl11-chloro-3,7,ll-trimethyltrideca-2,o-dienoate, and the like (seeExample 30), are converted by the processes of Part A above to thecorresponding ll-chloro-l-hydroxy, l1- chloro-l-acyloxy and ll-chloro-l-alkoxy derivatives.

EXAMPLE 33 The procedure of Example 30 is repeated using other C- 10,1 1unsaturated compounds described herein such as those of Examples 8-14,23 and 24 to obtain the corresponding 11- chloro-derivatives, e.g. ethyll 1-chloro-3,l l-dimethyl-7-ethyltrideca-2,6-dienoate, ethyl1l-chloro-2,3-methylene-3,7,1l-

trimethyldodec-o-enoate, ethyl l 1-chloro-3,l 1-dimethyl-7-ethyldodec-2-enoate, ethyl 11-chloro-2,3;6,7-bismethylene- 3,7,1l-trimethyldodecanoate, and the like.

EXAMPLE 34 1 gram of trans, trans ethyl3,7,1l-trimethyl-ll-hydroxydodeca-2,6-dienoate in 8 ml. of pyridine and2 ml. of triethylamine is treated with 1 ml. of acetyl chloride. Thismixture is allowed to stand for 15 hours at about 25 C and is thenpoured into ice water and extracted with methylene chloride. Theseextracts are washed well with water, dried over sodium sulfate andevaporated to yield trans, trans ethyl 3,7,1 1- trimethyl-ll-acetoxydodeca-2,6-dienoate.

Use of other acid chlorides, such as trimethylacetyl chloride, benzoylchloride, phenylacetyl chloride, and the like, yields the correspondingesters.

EXAMPLE 35 A. lnto a mixture of 2 g. of methyll0,1l-oxido-3,7,lltrimethyltridec'a-Z,6-dienoate in ml. of ether, thereis introduced a slow stream of hydrogen chloride for 1 hour at 0 C. Themixture is then allowed to stand at 0 C for 18 hours. Then the mixtureis washed with 5 percent aqueous sodium bicarbonate solution, dried oversodium sulfate and evaporated to an oil containing methyl 1l-chloro-lO-hydroxy- 3,7,11-trimethyltrideca-2,6-dienoate and methyl7,11- dichloro-10-hydroxy-3,7,11-trimethyltridec-2-enoate which arepurified and separated by preparative silica chromatography.

B. The process of Part A above is repeated with the exception of usingas the starting material methyl6,7-oxido-3,7,1ltrimethyltrideca-2,lO-dienoate and there is obtainedmethyl 7-chloro-6-hydroxy-3 ,7,1 l-trimethyltrideca-2,10-dienoate andmethyl 7,1l-dichloro-6-hydroxy-3,7,l l-trimethyltridec-Z- enoate.

C. By repeating the process of Example 34 with the exception of usingmethyl l1-chloro-10-hydroxy-3,7,1l-trimethyltrideca-2,6-dienoate ormethyl 7,1l-dichloro-lO-hydroxy- 3,7,1l-trimethyltridec-2-enoate as thestarting material, the corresponding IO-acylatesare obtained, erg.methyl llchloro-l0-acetoxy-3,7,1 1-trimethyltrideca-2,6-dienoate,

2. A compound according to claim 1 of the formula:
 3. A compoundaccording to claim 2 wherein each of R1, R2, R3 and R4 is methyl orethyl and R'' is hydrogen or lower alkyl.
 4. A compound according toclaim 3 wherein each of R1, R2 and R3 is methyl; R4 is methyl or ethyl;R'' is lower alkyl; and Z7 taken together with Z6 is a carbon-carbondouble bond.
 5. The compound, methyl10,11-methylene-3,7,11-trimethyltrideca-2,6-dienoate, according to claim4.
 6. A compound according to claim 3 wherein each of R1 and R3 ismethyl; each of R2 and R4 is ethyl; R'' is lower alkyl; and Z7 takentogether with Z6 is a carbon-carbon double bond.
 7. A compound accordingto claim 1 of the formula:
 8. A compound according to claim 7 whereineach of R1, R2, R3 and R4 is methyl or ethyl.
 9. A compound according toclaim 8 wherein Z7 taken together with Z6 is a carbon-carbon double bondand Z11 taken together with Z10 is a carbon-carbon double bond.
 10. Acompound according to claim 9 wherein each of R1, R2 and R3 is methyland R4 is methyl or ethyl.
 11. A compound according to claim 10 whereinR'' is hydrogen, methyl or ethyl.
 12. A compound according to claim 9wherein each of R1 and R3 is methyl and each of R2 and R4 is ethyl. 13.A compound according to claim 8 wherein Z11 taken together with Z10 isthe group